Indole acetic acid derivatives and their use as pharmaceutical agents

ABSTRACT

This invention is directed to indole acetic acid derivatives and their use in pharmaceutical compositions for the treatment of diseases such as diabetes, obesity, hyperlipidemia, and atherosclerotic disease. The invention is also directed to intermediates useful in preparation of indole acetic derivatives and to methods of preparation.

This application claims benefit of U.S. Provisional Application Ser. No.60/466,143, filed Apr. 28, 2003, the contents of which are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

This invention is directed to indole acetic acid derivatives and theiruse in pharmaceutical compositions for the treatment of diseases such asdiabetes, obesity, hyperlipidemia, and atherosclerotic disease. Theinvention is also directed to intermediates useful in preparation ofindole acetic derivatives and to methods of preparation.

BACKGROUND OF THE INVENTION

Type 2 diabetes is the more common form of diabetes, with 90-95% ofhyperglycemic patients experiencing this form of the disease. In type 2diabetes, there appears to be a reduction in the pancreatic β-cell mass,several distinct defects in insulin secretion, and a decrease in tissuesensitivity to insulin. The symptoms and consequences of this form ofdiabetes include fatigue, frequent urination, thirst, blurred vision,frequent infections and slow healing of sores, diabetic nerve damage,retinopathy, micro and macro blood vessel damage, and heart and renaldisease.

Resistance to the metabolic actions of insulin is one of the keyfeatures of type 2 diabetes. Insulin resistance is characterized byimpaired uptake and utilization of glucose in insulin-sensitive targetorgans, for example, adipocytes and skeletal muscle, and by impairedinhibition of hepatic glucose output. Functional insulin deficiency,insulin resistance in the periphery, and the failure of insulin tosuppress hepatic glucose output results in fasting hyperglycemia.Pancreatic β-cells compensate for the insulin resistance by secretingincreased levels of insulin. However, the β-cells are unable to maintainthis high output of insulin, and eventually, the glucose-induced insulinsecretion falls, leading to the deterioration of glucose homeostasis andto the subsequent development of overt diabetes. Hyperinsulinemia isalso linked to insulin resistance, hypertriglyceridemia, lowhigh-density lipoprotein (HDL) cholesterol, and increased plasmaconcentration of low-density lipoproteins (LDL). The association ofinsulin resistance and hyperinsulinemia with these metabolic disordershas been termed “Syndrome X,” and has been strongly linked to anincreased risk of hypertension and coronary artery disease.

Obesity is an excessive accumulation of adipose tissue. Excess adiposetissue is associated with the development of serious medical conditions,for example, type 2 diabetes, hypertension, coronary artery disease,hyperlipidemia, obesity, and certain malignancies. The adipocyte mayalso influence glucose homeostasis through the production of tumornecrosis factor α (TNFα) and other molecules.

Atherosclerotic disease is known to be caused by a number of factors,for example, hypertension, diabetes, low levels of HDL, and high levelsof LDL. Atherosclerotic-related diseases include cardiovascular disease,coronary heart disease (CHD), cerebrovascular disease, and peripheralvessel disease. Coronary heart disease includes CHD death, myocardialinfarction, and coronary revascularization. Cerebrovascular diseaseincludes ischemic or hemorrhagic stroke, and transient ischemic attacks.

Accordingly, despite the presence of some pharmaceuticals that are usedto treat these diseases, there remains a need for new pharmaceuticalsthat are both safe and effective agents for the treatment of disease,and for useful methods to prepare them.

The present invention relates to compounds which are useful in thetreatment of diabetes and related disorders such as Syndrome X, impairedglucose tolerance, impaired fasting glucose, and hyperinsulinemia;obesity; atherosclerotic disease, dyslipidemia, and related disorderssuch as hypertriglyceridemia, low HDL cholesterol, andhypercholesteremia; cardiovascular disease; and cerebrovascular disease.

DESCRIPTION OF THE INVENTION

The invention provides indole acetic acid derivatives of Formula (Ia)and Formula (Ib)

wherein

-   R¹ is H, C₁-C₆ alkyl, or benzyl;-   R² is H or C₁-C₆ alkyl;-   R³ is H or C₁-C₄alkyl;-   R⁴ is H, C₁-C₄ alkyl, or C₁-C₄ acyl;-   Y is O or NR⁵;-   R⁵ is H or C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl;-   n is 2, 3, or 4;-   Ar is a ring radical selected from phenyl and a 6-membered    heteroaryl ring containing up to three N atoms,    -   said Ar being optionally substituted at any available position        by 1 to 5 independently selected R⁶ groups,        -   and        -   optionally fused to a 5- or 6-membered saturated carbocyclic            ring,            -   a 5- or 6-membered unsaturated carbocyclic ring, or            -   a 5- or 6-membered heterocyclic ring containing up to 3                additional heteroatoms selected from N, O, and S,            -   wherein                -   said fused ring may be optionally substituted at any                    available position by 14 independently selected R⁷                    groups;-   R⁶ is selected from the group    -   OH,    -   SH,    -   halo,    -   CN,    -   NO₂,    -   C(═O)OH,    -   C(═O)OC₁-C₆ alkyl,    -   C(═O)OC₃-C₆ cycloalkyl,    -   NR⁸R⁹,    -   C(═O)NR⁸R⁹,    -   C(═S)NR⁸R⁹,    -   C₁-C₆alkyl optionally substituted with halo, OH, NR⁸R⁹, or C₁-C₆        alkoxy,    -   C₁-C₆ haloalkyl,    -   C₁-C₆ alkoxy,    -   C₁-C₆ thioalkyl,    -   C₂-C₆ alkenyl,    -   C₁-C₆ haloalkoxy,    -   C₃-C₆ cycloalkyl,    -   C₃-C₆ cycloalkoxy,    -   phenoxy optionally substituted on the phenyl ring with halo,        C₁-C₆ alkyl, or C₁-C₆ alkoxy, and    -   a mono or bicyclic ring radical selected from the group        consisting of        -   phenyl optionally fused to            -   a 5- or 6-membered saturated or partially unsaturated                carbocyclic ring, or            -   a 5- or 6-membered saturated or partially unsaturated                heterocyclic ring containing from 1-3 heteroatoms                selected from N, O, and S, and        -   a 5- or 6-membered heterocyclic ring radical containing up            to 4 heteroatoms selected from N, O, or S, optionally fused            to            -   a 5- or 6-membered saturated or partially unsaturated                carbocyclic ring, or            -   a 5- or 6-membered saturated or partially unsaturated                heterocyclic ring containing from 1-3 heteroatoms                selected from N, O, and S,        -   said mono or bicyclic ring radical being optionally            substituted with up to 5 of the following groups            -   halo,            -   hydroxy,            -   oxo,            -   CN,            -   C₁-C₆ alkyl optionally substituted with halo, OH, NR⁸R⁹,                or C₁-C₆ alkoxy,            -   C₁-C₆ haloalkyl,            -   C₁-C₆ alkoxy,            -   C₁-C₆ thioalkyl            -   C₁-C₆ haloalkoxy,            -   C₃-C₆ cycloalkyl,            -   C₃-C₆ cycloalkoxy,            -   C₁-C₆ acyl,            -   C(═O)OH,            -   CH₂C(═O)OH,            -   NR⁸R⁹            -   C(═O)NR⁸R⁹,            -   C(═O)OC₁-C₆ alkyl, and            -   C(═O)OC₃-C₆ cycloalkyl;-   R⁷ is selected from the group    -   oxo,    -   hydroxy,    -   halo,    -   CN,    -   NR⁸R⁹,    -   C₁-C₆ alkyl optionally substituted with OH, NR⁸R⁹, or C₁-C₆        alkoxy,    -   C₁-C₆ haloalkyl,    -   C₁-C₆alkoxy,    -   C₁-C₆ thioalkyl,    -   C₁-C₆ haloalkoxy,    -   C₃-C₆ cycloalkyl, and    -   C₃-C₆ cycloalkoxy;-   R³ and R⁹ are independently selected from    -   H,    -   C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl,    -   C₁-C₆ acyl,    -   benzyl optionally substituted with halo, C₁-C₆ alkoxy,        (C₁-C₆)alkyl, CN, NH₂, N[(C₁-C₃)alkyl]₂, NO₂, or CF₃,    -   C₃-C₆ cycloalkyl, and    -   phenyl optionally substituted with halo, C₁-C₆ alkoxy,        (C₁-C₆)alkyl, CN, N[(C₁-C₃)alkyl]₂, NO₂, or CF₃,-   or-   R⁸ and R⁹ may be taken together with the nitrogen atom to which they    are attached to form a 5- or 6-membered heterocyclic ring optionally    interrupted by NR⁵ or O;    or the pharmacologically acceptable esters and salts thereof.    Definitions

The terms identified above have the following meaning throughout:

The term “halo” means F, Cl, Br, or I.

The terms “C₁-C₃ alkyl,” “C₁-C₄ alkyl,” and “C₁-C₆alkyl” mean a straightor branched saturated hydrocarbon carbon chain of from 1 to about 3carbon atoms, from 1 to about 4 carbon atoms, or from 1 to about 6atoms, respectively. Examples of such groups include, but are notlimited to, methyl, ethyl, isopropyl, sec-butyl, 2-methylpentyl,n-hexyl, and the like.

The term “C₂-C₆ alkenyl” means a straight or branched unsaturatedhydrocarbon carbon chain of from 2 to about 6 carbon atoms. Examples ofsuch groups include, but are not limited to, vinyl, allyl, isopropenyl,2-butenyl, 3-ethyl-2-butenyl, 4-hexenyl, and the like.

The term “C₁-C₆ haloalkyl” means a C₁-C₆ alkyl group substituted by 1 to3 halogen atoms or fluorine up to the perfluoro level. Examples of suchgroups include, but are not limited to, trifluoromethyl,tetrafluoroethyl, 1,2-dichloropropyl, 5-bromopentyl, 6-iodohexyl, andthe like.

The term “C₃-C₆ cycloalkyl” means a saturated carbocyclic ring system offrom 3 to about 6 carbon atoms. Examples of such groups include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andthe like.

The terms “C₁-C₄ acyl” and “C₁-C₆ acyl” means a linear or branchedsaturated carbon group having from about 1 to about 4 C atoms or fromabout 1 to about 6 C atoms, respectively, said carbon group beingattached to the core molecule through the C atom of a C═O group.Examples of such groups include, but are not limited to, acetyl,propionyl, n-butanoyl, 2-methylpentantoyl, and the like

The term “C₁-C₆ alkoxy” means a linear or branched saturated carbongroup having from 1 to about 6 C atoms, said carbon group being attachedto an O atom. The O atom is the point of attachment of the alkoxysubstituent to the rest of the molecule. Such groups include, but arenot limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

The term “C₁-C₆ thioalkyl” means a linear or branched saturated carbongroup having from 1 to about 6 C atoms, said carbon group being attachedto an S atom. The S atom is the point of attachment of the thioalkylsubstituent to the rest of the molecule. Such groups include, but arenot limited to, methylthio, propylthio, hexylthio, and the like.

The term “C₁-C₆ haloalkoxy” means a C₁-C₆alkoxy group furthersubstituted on C with 1 to 3 halogen atoms or fluorine up to theperfluoro level.

The term “C₃-C₆ cycloalkoxy” means a C₃-C₆ cycloalkyl group attached toan O atom. The O atom is the point of attachment of the cycloalkoxygroup with the rest of the molecule.

The term “phenoxy” means a phenyl group attached to an O atom. The Oatom is the point of attachment of the phenoxy group to the rest of themolecule.

The term “6-membered heteroaryl ring” means a 6-membered monocyclicheteroaromatic ring radical containing 1-5 carbon atoms and up to theindicated number of N atoms. Examples of 6-membered heteroaryl ringsinclude, but are not limited to, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl, and the like.

The term “5- or 6-membered heterocyclic ring” means a 5 or 6-memberedring containing 1-5 C atoms and up to the indicated number of N, O and Satoms, and may be aromatic, partially saturated, or fully saturated.

When the 5- or 6-membered heterocyclic ring is attached to the rest ofthe molecule as a substituent, it becomes a radical. Examples of 5- or6-membered heteroaryl ring radicals include, but are not limited to,furyl, pyrrolyl, thienyl, pyrazolyl, isoxazolyl, imidazolyl, oxazolyl,thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, and the like. Examples ofpartially unsaturated 5- or 6-membered heterocyclic ring radicalsinclude, but are not limited to, dihydropyranyl, pyrrolinyl,pyrazolinyl, imidazolinyl, dihydrofuryl, and the like. Examples ofsaturated 5- or 6-membered heterocyclic ring radicals include, but arenot limited to, pyrrolidinyl, tetrahydropyridyl, piperidinyl,morpholinyl, tetrahydrofuryl, tetrahydrothienyl, piperazinyl, and thelike. The point of attachment of the radical may be from any available Cor N atom of the ring to the rest of the molecule.

When the 5- or 6-membered heterocyclic ring is fused to another ringcontained in the rest of the molecule, it forms a bicyclic ring.Examples of such 5- and 6-membered heterocyclic fused rings include, butare not limited to, pyrrolo, furo, pyrido, piperido, thieno, and thelike. The point of fusion is at any available face of the heterocyclicring and parent molecule.

Examples of compounds of Formulae (Ia) and (Ib) may be found in thepreparative examples described below and in Table 1. The compoundsdescribed in the examples are intended to be representative of theinvention, and it will be understood that the scope of the invention isnot limited by the scope of the examples. Those skilled in the art willrecognize that the invention may be practiced with variations on thedisclosed structures, materials, compositions and methods, and suchvariations are regarded as within the ambit of the invention.

A salt of a compound of Formulae (Ia) or (Ib) may be prepared in situduring the final isolation and purification of a compound, or byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid and isolating the salt thus formed.Likewise, when a compound of Formulae (Ia) or (Ib) contains a carboxylicacid moiety (e.g., R¹═CH₂CO₂H), a salt of said compound of Formulae (Ia)or (Ib) may be prepared by separately reacting it with a suitableinorganic or organic base and isolating the salt thus formed. The term“pharmaceutically acceptable salt” refers to a relatively non-toxic,inorganic or organic acid addition salt of a compound of the presentinvention (see, e.g., Berge, et al., J. Pharm. Sci. 66:1-19, 1977).

Representative salts of the compounds of Formulae (Ia) and (Ib) includethe conventional non-toxic salts and the quaternary ammonium salts whichare formed, for example, from inorganic or organic acids or bases bymeans well known in the art. For example, such acid addition saltsinclude acetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate,maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate,tartrate, thiocyanate, tosylate, undecanoate, and the like.

Base salts include, for example, alkali metal salts such as potassiumand sodium salts, alkaline earth metal salts such as calcium andmagnesium salts, and ammonium salts with organic bases such asdicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogencontaining groups in the conjugate base may be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates like dimethyl,diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halidessuch as decyl, lauryl, myristyl and strearyl chlorides, bromides andiodides; aralkyl halides like benzyl and phenethyl bromides, and thelike.

The esters of Formulae (Ia) and (Ib) in the present invention arenon-toxic, pharmaceutically acceptable esters, for example, alkyl esterssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentylesters. Additional esters such as, for example, methyl ester orphenyl-C₁-C₅ alkyl may be used. A compound of Formulae (Ia) or (Ib) maybe esterified by a variety of conventional procedures including reactingthe appropriate anhydride, carboxylic acid, or acid chloride with thealcohol group of the Formulae (Ia) or (Ib) compound. The appropriateanhydride may be reacted with the alcohol in the presence of a base tofacilitate acylation such as 1,8-bis[dimethylamino]naphthalene orN,N-dimethylaminopyridine. An appropriate carboxylic acid may be reactedwith the alcohol in the presence of a dehydrating agent such asdicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide,or other water soluble dehydrating agents which are used to drive thereaction by the removal of water, and optionally, an acylation catalyst.Esterification may also be effected using the appropriate carboxylicacid in the presence of trifluoroacetic anhydride and optionally,pyridine, or in the presence of N,N-carbonyldiimidazole with pyridine.Reaction of an acid chloride with the alcohol may be carried out with anacylation catalyst such as 4-DMAP or pyridine.

One skilled in the art would readily know how to successfully carry outthese as well as other methods of esterification of alcohols.

Additionally, sensitive or reactive groups on a compound of Formulae(Ia) or (Ib) may need to be protected and deprotected during any of theabove methods for forming esters. Protecting groups in general may beadded and removed by conventional methods well known in the art (see,e.g., T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis; Wiley: New York, (1999)).

The compounds of Formulae (Ia) and (Ib) may contain one or moreasymmetric centers, depending upon the location and nature of thevarious substituents desired. Asymmetric carbon atoms may be present inthe (R) or (S) configuration. Preferred isomers are those with theabsolute configuration which produces a compound of Formulae (Ia) or(Ib) with the more desirable biological activity. In certain instances,asymmetry may also be present due to restricted rotation about a givenbond, for example, the central bond adjoining two aromatic rings of thespecified compounds.

Substituents on a ring may also be present in either cis or trans form,and a substituent on a double bond may be present in either Z or E form.

It is intended that all isomers (including enantiomers anddiastereomers), either by nature of asymmetric centers or by restrictedrotation as described above, as separated, pure or partially purifiedisomers or racemic mixtures thereof, be included within the scope of theinstant invention. The purification of said isomers and the separationof said isomeric mixtures may be accomplished by standard techniquesknown in the art.

The particular process to be utilized in the preparation of thecompounds of this invention depends upon the specific compound desired.Such factors as the selection of the specific X moiety, and the specificsubstituents possible at various locations on the molecule, all play arole in the path to be followed in the preparation of the specificcompounds of this invention. Those factors are readily recognized by oneof ordinary skill in the art.

In general, the compounds used in this invention may be prepared bystandard techniques known in the art, by known processes analogousthereto, and/or by the processes described herein, using startingmaterials which are either commercially available or producibleaccording to routine, conventional chemical methods. The followingpreparative methods are presented to aid the reader in the synthesis ofthe compounds of the present invention.

General Methods of Preparation

Compounds of Formulae (Ia) and (Ib) can be prepared by the generalmethods outlined in the schemes below. Unless specifically definedotherwise, R¹-R⁹, Y, n, and Ar have the meanings described above for thecompounds of Formulae (Ia) and (Ib).

In Scheme 1, for example, compounds of Formula (Ia) can be prepared byeither of the two routes illustrated. In Method A, a hydroxy or aminocompound of Formula (II) is allowed to react with a substituted alkyleneof Formula (III), optionally in the presence of a base, to provide theintermediate of Formula (IV). This compound is then allowed to reactwith the 5-hydroxyindole of Formula (V), optionally in the presence ofbase, to give the compound of the invention of Formula (Ia).

Alternatively, as shown in Method B, the reaction of the compound ofFormula (VI) with a compound of Formula (VII), optionally in thepresence of a base, gives an intermediate of Formula (VIII). This isallowed to react with the 5-hydroxyindole of Formula (V) under Mitsunobuconditions, (e.g., DEAD, TPP) to provide the compound of Formula (Ia).

In a similar fashion, compounds of Formula (Ib) can be prepared byanalogous procedures illustrated in Scheme 2. In Method A, thepreviously described intermediate of Formula (IV) is allowed to reactwith the 6-hydroxyindole of Formula (IX) in the presence of a base suchas cesium carbonate, to give the compound of Formula (Ib).

Alternatively, the intermediate of Formula (VIII), prepared aspreviously described, is allowed to react under Mitsunobu conditions(e.g., DEAD, TPP) to provide the compounds of Formula (Ib).

Intermediates that are not commercially available may be prepared bymethods known in the art or methods analogous thereto. For example,5-hydroxyindole intermediates of Formula (V) are generally prepared asshown in Scheme 3. The protected hydroxyindole is allowed to react witha strong base, such as an alkyl magnesium halide, followed by an alkylhalide of Formula (XI) [where hal is I, Br, or Cl] to provide the3-alkylsubstituted indole of Formula (XII). N-alkylation of (XII) with acompound of Formula (XIII) in the presence of base provides theintermediate of Formula (XIV). Deprotection of (XIV) gives the compoundof Formula (V). If desired, compounds of Formula (V) where R¹ is C₁-C₆alkyl, may be hydrolyzed to the corresponding acid compounds of Formula(XV) [(V) where R¹ is H].

Intermediate 6-hydroxyindoles of Formula (IX) are generally prepared asshown in Scheme 4. Methoxy aniline of Formula (XVI) is acylated underFriedel-Crafts conditions to give, upon workup, the aminochloroacetophenone of Formula (XVII). Alkylation of the amine group ofFormula (XVII) using a reagent of Formula (XVIII), such as dimethylsulfate, optionally in the presence of a base, provides the intermediateof Formula (XIX). Ring closure of (XIX) with a base such as sodiumhydride give the indolinone of Formula (XX). Reaction of (XX) with aWadsworth-Emmons reagent of Formula (XXI) gives the indole acetic acidderivative of Formula (XXII). Demethylation of (XXII) by standardmethods (e.g., BBr₃) provides the desired 6-hydroxyindole intermediateof Formula (IX). Hydrolysis of a Formula (IX) compound where R¹ is C₁-C₆alkyl may be carried out, if desired, under standard conditions toprovide the corresponding carboxylic acid compound of Formula (XXIII)[Formula (IX) where R¹ is H].

The preparation of intermediates of Formula (II) where Ar is phenyl, Yis O, and R⁶ is a thiazolyl ring, is described in PCT/US03/40842,incorporated by reference herein, and is further illustrated in Schemes5 and 6. In Scheme 5, a cyanophenol of Formula (XXIV) is allowed toreact sequentially with H₂S and an appropriately substituted ketone,typically an alpha-haloketone of Formula (XXV), to give the phenol ofFormula (XXVI) [(II), where Ar is phenyl, Y is O, and one R⁶ is anoptionally substituted thiazolyl radical].

Similarly, in Scheme 6, Formula (II) compounds in which Ar is phenyl, Yis O, and one R⁶ group is an optionally substituted oxazole is preparedas shown in Scheme 6, also starting from the cyanophenol of Formula(XXIV). Basic peroxide hydrolysis of (XXIV) gives the amide of Formula(XXVII); reaction with the ketone of Formula (XXV) gives the desiredintermediate of Formula (XXVIII) [(II), where Ar is phenyl, Y is O, andone R⁶ is an optionally substituted oxazolyl radical].

The chemistry described in Schemes 5 and 6 may also be carried out onappropriately substituted Formulae (Ia) and (Ib) compounds, namelyFormulae (Ia) or (Ib) in which one of the R⁶ substituents is cyano. Anexample of such transformation is shown in Scheme 7. The compound ofFormula (XXIX) [(Ia) where R⁶ substituent is cyano] is subjected tosequental treatment with H₂S, a ketone of Formula (XXV), and basichydrolysis to give the Formula (XXX) compound [(Ia) where R⁶ is anoptionally substituted thiazolyl radical and R¹ is H].

Preparation of Formulae (Ia) and (Ib) compounds in which R⁶ is a mono orbicyclic ring radical may be prepared from the respective Formulae (Ia)and (Ib) compounds in which R⁶ is halo. An example is illustrated inScheme 8, in which a compound of Formula (XXXI) [(Ia) where R⁶ is Cl] isallowed to react with a boronic acid or boronic ester under Suzukiconditions [base and Pd catalyst such as PdCl₂(dppf)] to give, afterhydrolysis, the compound of Formula (XXXIII) [(Ib) where R⁶ is anoptionally substituted mono or bicyclic ring radical and R¹ is H].

By a using the above schemes, alone or in combination, and preparativemethods known in the art, compounds of the present invention can bemade. The following experimental examples are presented to illustratethe invention described herein, but should not be construed as limitingthe scope of the invention in any way.

Experimental Procedures

Air and moisture sensitive liquids and solutions were transferred viasyringe or cannula, and introduced into reaction vessels through rubbersepta. Commercial grade reagents and solvents were used without furtherpurification. The term “concentration under reduced pressure” refers touse of a Buchi rotary evaporator at approximately 15 mm of Hg. Alltemperatures are reported uncorrected in degrees Celsius (° C.). Thinlayer chromatography (TLC) was performed on EM Science pre-coatedglass-backed silica gel 60 A F-254 250 μm plates. Column chromatography(flash chromatography) was performed on a Biotage system using 32-63micron, 60 A, silica gel pre-packed cartridges. Purification usingpreparative reversed-phase HPLC chromatography were accomplished using aGilson 215 system and a YMC Pro-C18 AS-342 (150×20 mm I.D.) column.Typically, the mobile phase used was a mixture of H₂O (A) and MeCN (B).The water could be mixed or not with 0.1% TFA. A typical gradient was:Time Flow [min.] A: % B: % [mL/min.] 0.50 90.0 10.0 1.0 11.00 0.0 100.01.0 14.00 0.0 100.0 1.0 15.02 100.0 0.0 1.0

Unless otherwise specified, chiral analytical HPLC experiments wereperformed using one the two following methods using a Varian Pro Star1200:

A: Column: Chiracel AD, 4.6 (I.D.)×250 mm

-   -   Mobile Phase: A: 0.1% TFA in hexanes; B: 0.1% TFA in i-PrOH;    -   Isocratic: 95% A (5% B), 20 min.    -   Flow Rate: 1.5 mL/min    -   Detector (UV): 284 nm

B: Column: Chiracel AD, 4.6 (I.D.)×250 mm

-   -   Mobile Phase: A: 0.1% TFA in hexanes; B: 0.1% TFA in i-PrOH    -   Isocratic: 95% A (5% B), 25 min.    -   Flow Rate: 1.0 mL/min    -   Detector (UV): 284 nm

Electron impact mass spectra (EI-MS or GC-MS) were obtained with aHewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard5890 Gas Chromatograph with a J & W DB-5 column (0.25 μM coating; 30m×0.25 mm). The ion source was maintained at 250° C. and spectra werescanned from 50-800 amu at 2 sec per scan. High pressure liquidchromatography-electrospray mass spectra (LC-MS) were obtained using aHewlett-Packard 1100 HPLC equipped with a quaternary pump, a variablewavelength detector set at 254 nm, a YMC pro C-18 column (2×23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrosprayionization. Spectra were scanned from 120-1200 amu using a variable iontime according to the number of ions in the source. The eluents were A:2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrilewith 0.018% TFA. Gradient elution from 10% to 95% B over 3.5 minutes ata flowrate of 1.0 mL/min was used with an initial hold of 0.5 minutesand a final hold at 95% B of 0.5 minutes. Total run time was 6.5minutes. For consistency in characterization data, the retention time(RT) is reported in minutes at the apex of the peak as detected by theUV-Vis detector set at 254 nm.

Routine one-dimensional NMR spectroscopy was performed on 300 or 400 MHzVarian Mercury-plus spectrometers. The samples were dissolved indeuterated solvents obtained from Cambridge Isotope Labs, andtransferred to 5 mm ID Wilmad NMR tubes. The spectra were acquired at293 K. The chemical shifts were recorded on the ppm scale and werereferenced to the appropriate residual solvent signals, such as 2.49 ppmfor DMSO-d₆, 1.93 ppm for CD₃CN, 3.30 ppm for CD₃OD, 5.32 ppm forCD₂Cl₂, and 7.26 ppm for CDCl₃ for ¹H NMR spectra, and 39.5 ppm forDMSO-d₆, 1.3 ppm for CD₃CN, 49.0 ppm for CD₃OD, 53.8 ppm for CD₂Cl₂, and77.0 ppm for CDCl₃ for ¹³C NMR spectra. General methods of preparationare illustrated in the reaction schemes, and by the specific preparativeexamples that follow.

Abbreviations and Acronyms

When the following abbreviations are used throughout the disclosure,they have the following meaning:

-   Ac acetyl-   AcOH acetic acid-   ADDP 1,1′-[azodicarbonyl]dipiperidine-   Boc t-butoxycarbonyl-   Bu butyl-   CDCl₃ deuterochloroform-   Celite® registered trademark of Celite Corp. brand of diatomaceous    earth-   CI chemical ionization-   d doublet-   dd doublet of doublet-   ddd doublet of doublet of doublet-   de diastereomeric excess-   DAST (diethylamino) sulfur trifluoride-   DEAD diethyl azodicarboxylate-   DIA diisopropylamine-   DIAD diisopropyl azodicarboxylate-   DMAP 4-(N,N-dimethyl)amino pyridine-   DME dimethoxyethane-   DMF N,N-dimethyl formamide-   DMSO dimethylsulfoxide-   DMSO-d₆ dimethylsulfoxide-d₆-   DOWEX® 66 Dowex hydroxide, weakly basic anion, macroporous, 25-50    mesh-   dppf 1,1′-bis(diphenylphosphino)ferrocene-   Drierite® anhydrous calcium sulfate (W. A. Hammond Drierite Co.)-   ee enantiomeric excess-   EI electron impact ionization-   EI-MS electron impact-mass spectrometry-   Et ethyl-   EtOH ethanol-   EtOAc ethyl acetate-   EtSH ethane thiol-   g gram-   GCMS gas chromatography-mass spectrometry-   h hour(s)-   ¹H NMR proton nuclear magnetic resonance-   Hex hexanes-   HPLC high performance liquid chromatography-   LC-MS liquid chromatography/mass spectroscopy-   LDA lithium diisopropylamide-   m multiplet-   M molar-   m/z mass over charge-   Me methyl-   MeCN acetonitrile-   mg milligram-   MHz megahertz-   min minute(s)-   mol mole-   mmol millimole-   MS mass spectrometry-   N normal-   NMR nuclear magnetic resonance-   NaOAc sodium acetate-   Pd/C palladium on carbon-   PdCl₂(dppf).CH₂Cl₂    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex    with dichloromethane (1:1)-   Ph phenyl-   PPh₃ triphenylphosphine-   ppm parts per million-   psi pounds per square inch-   Pr propyl-   q quartet-   qt quintet-   quant. quantitatve-   R_(f) TLC retention factor-   rt room temperature-   RT retention time (HPLC)-   s singlet-   TBS tert-butyldimethylsilyl-   TBSCl tert-butyldimethylsilyl chloride-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   TMS tetramethylsilane-   TPP triphenylphosphine-   v/v volume per unit volume-   vol volume-   w/w weight per unit weight.

PREPARATIVE EXAMPLES

Step 1: C-Alkylation Example 1 Preparation of5-(benzyloxy)-3-methyl-1H-indole

To a solution of 5-benzyloxyindole (19.8 g, 88.68•mmol) in THF (200 mL)pre-cooled with an ice bath, was added a 3.0 M solution of ethylmagnesium bromide in diethyl ether (44.3 mL, 133.02 mmol). The ice bathwas removed and the resulting mixture was gradually warmed to rt over 5h. The reaction mixture was cooled to 0° C. and iodomethane (37.8 g,266.04 mmol) was added. The mixture was warmed to rt and stirred for 12h. The reaction mixture was quenched by the addition of saturatedaqueous ammonium chloride solution (50 mL). The reaction mixture wasdiluted with diethyl ether (150 mL), and then washed with water and abrine solution consecutively. The combined organic layers were driedover magnesium sulfate, filtered, and then concentrated via rotaryevaporation to give a dark brownish solid. The crude mixture waspurified on silica gel (95:5 hexane:dichloromethane) to give the titlecompound (12.6 g, 60%) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 7.79(br s, 1H), 7.50 (d, 2H), 7.45 (m, 3H), 7.32 (s, 1H), 7.11 (d, 1H), 6.95(m, 2H), 5.13 (s, 2H), 2.31 (s, 3H).

Example 2 Preparation of 5-(benzyloxy)-3-ethyl-1H-indole

The title compound was prepared according to the method described inExample 1 substituting iodoethane for iodomethane. ¹H NMR (CDCl₃) δ 7.79(br s, 1H), 7.59 (d, 2H), 7.42 (m, 3H), 7.24 (m, 2H), 7.04 (d, 1H), 6.95(m, 1H), 5.21 (s, 2H), 2.83 (q, 2H), 1.42 (t, 3H).

Step 2: N-Alkylation Example 3 Preparation of2-(5-benzyloxy-indol-1-yl)-propionic acid methyl ester

To a solution of 5-benzyloxyindole (13.5 g, 60.46 mmol) in DMF (300 mL)was added sodium hydride (60% dispersion in mineral oil, 3.63 g, 90.7mmol). The resulting suspension was stirred at rt for 1 h after whichmethyl 2-bromopropionate (11.1 g, 66.51 mmol) was added. The resultingsuspension was stirred at rt for 6 h. The reaction mixture was quenchedwith sat. aqueous ammonium chloride solution (25 mL), and diluted with200 mL of EtOAc. The organic layer was washed with water three times.The aqueous layer was extracted again with EtOAc. The combined organiclayers were dried over magnesium sulfate, filtered, and concentrated viarotary evaporation. The resulting brown oil was purified on silica gel(EtOAc/hexanes 1:1) to give the title compound as a brownish oil (15.3g, 82%). LC/MS m/z 310 (M+H)⁺, RT 4.04 min.

¹H NMR (400 MHz, Acetone-d₆) δ 7.57 (d, 2H), 7.23-7.41 (m, 5H), 7.19 (d,1H), 6.84 (d, 1H), 6.40 (d, 1H), 5.37 (q, 1H), 5.17 (s, 2H), 3.66 (s,3H), 1.79 (d, 3H).

Example 4 Preparation of (R)-2-(5-benzyloxy-indol-1-yl)-propionic acid

A suspension of 5-benzyloxyindole (105.29 g, 0.448 mol) and KOH (88.72g, 1.344 mol) in DMSO (640.0 mL) was heated to ˜120° C. and stirred for25 minutes. The resulting dark colored solution was cooled to rt andthen to 15-18° C. in an ice/water bath. To this mixture was added(S)-bromopropionic acid (46.47 mL, 0.515 mol) over 10 minutes,maintaining the temperature below 35° C. The resulting reaction mixturewas stirred at −30° C. for 1.5 h. The reaction was monitored by reversephase HPLC. Upon completion, the reaction mixture was quenched bypouring into ice/water (1.2 L). The resulting mixture was extracted withethyl acetate (2×500 mL, 1×250 mL). The combined organic layers werewashed with water (3×500 mL), brine (350 mL), dried over anhydroussodium sulfate, filtered, and concentrated to dryness to give 135 g ofthe crude product which was found to have an ee of ˜80%. This mixturewas purified by silica gel chromatography using a gradient ofdichloromethane to 8% MeOH/dichloromethane giving 115 g of(R)-2-(5-benzyloxy-indol-1-yl)propionic acid, containing 10% of the(S)enantiomer.

This mixture was further enriched to give provide the (R) enantiomer ingreater optical purity by the carrying out the following procedure:

The mixture was dissolved in dichloromethane/hexanes (294/294 mL) andstirred at rt for 2 days. The resulting racemic solid mixture wasremoved by filtration. The filtrate contained the desired enantiomer(90% ee). The filtrate was concentrated to dryness (at ˜35° C.) to give91 g of the desired product. The above precipitation process wasrepeated with dichloromethane/hexanes (273/575 mL). After filtration andwashing with dichloromethane/hexanes (30 mL), the combined filtrateswere concentrated to give 82.9 g of the desired product (95% ee). ¹H NMR(400 MHz, DMSO-d₆) δ 7.43 (d, 2H), 7.38 (m, 3H), 7.30 (m, 2H), 7.13 (s,1H), 6.82 (d, 1H), 6.38 (s, 1H), 5.25 (q, 1H), 5.08 (s, 2H), 1.70 (d,3H); LC/MS (+esi) m/z 296.1 (M+H)⁺, RT 3.06 min.

Chiral HPLC conditions for indole propionic acid: Column: Chiracel AD,4.6 (I.D.)×250 mm; Mobile Phase: A: 0.1% TFA in Hexanes; B: 0.1% TFA inIPA; Gradient: 90-65% A (10-35% B) in 21 min.; Flow rate: 1.0 mL/min;Detector (UV): 284 nm; retention time of desired enantiomer: 13.09 min.

Reverse Phase HPLC conditions: Column: YMC-Pack ProC18 (AS-300), 50×4.6mm (I.D.), S-5 μm, 12 nm (No. 040506614); Mobile Phase: A: 0.1% TFA inwater; B: 0.1% TFA in acetonitrile; Gradient: 90-5% A (10-95% B) in 7min.; Flow rate: 4.0 mL/min; Detector (UV): 220 nm. Retention time oftitle compound: 3.53 min.

The absolute stereoisomeric configuration of the target compound wasdetermined by single crystal X-ray analysis of its R-α-methylbenzylaminesalt.

Example 5 Preparation of [5-(benzyloxy)-1H-indol-1-yl]acetic acid methylester

To a solution of 5-benzyloxyindole (1.67 g, 7.489 mmol) in DMF (50 mL)was added sodium hydride (60% dispersion in mineral oil, 389 mg, 9.735mmol). The resulting suspension was stirred at rt for 1 h at which timemethyl bromoacetate (1.26 g, 8.238 mmol) was added. The resultingsolution was stirred at rt for 4.5 h. The reaction was quenched withsat. aqueous ammonium chloride solution (25 mL), and diluted with EtOAc(50 mL). The organic layer was washed three times with water. Theaqueous layer was extracted with EtOAc again and the combined organiclayers were dried over magnesium sulfate, filtered, and concentrated viarotary evaporation. The resulting brown oil was purified on silica gel(hexanes/EtOAc 1:1) to give the title compound as a brownish oil (1.64g, 74%). LC/MS m/z 296 (M+H)⁺, RT 3.21 min; ¹H NMR (400 MHz, CDCl₃) δ7.35-7.37 (m, 2H), 7.23-7.30 (m, 3H), 7.02-7.08 (m, 2H), 6.95 (d, 1H),6.87 (dd, 1H), 6.37 (dd, 1H), 5.01 (s, 2H), 4.72 (s, 2H), 3.64 (s, 3H).

Example 6 Preparation of 2-(5-benzyloxy-3-methyl-indol-1-yl)-propionicacid methyl ester

This compound was prepared according to the method outlined in Example5, using the compound described in Example 1 and 2-bromoproprionate asstarting materials. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (m, 2H), 7.46 (m,3H), 7.24 (d, 1H), 7.19 (d, 1H), 7.08 (s, 1H), 7.03 (dd, 1H), 5.20 (s,2H), 5.16 (1, 1H), 3.75 (s, 3H), 2.40 (s, 3H), 1.84 (d, 3H).

Step 3: Deprotection to Phenol Example 7 Preparation of2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester

To a solution of 2-(5-benzyloxy-indol-1-yl)-propionic acid methyl ester(Example 3, 20.0 g, 64.7 mmol) in absolute ethanol (150 mL) was addedPd(OH)₂ (2.0 g, 10 wt %) suspended in ethanol (50 mL). Ammonium formate(8.1 g, 129.3 mmol) was added and the resulting mixture was heated to60° C. for 4 h. The reaction mixture was cooled to rt and the palladiumwas filtered through a plug of silica gel. The filtrate was concentratedto give a light yellow oil which was used in the following step withoutfurther purification (13 g, 92%). LC/MS m/z 220 (M+H)⁺, RT 8.01 min; ¹HNMR (400 MHz, acetone-d₆) δ 7.78 (br s, 1H), 7.28 (d, 1H), 7.20 (d, 1H),6.97 (d, 1H), 6.77 (dd, 1H), 6.36 (d, 1H), 5.23 (q, 1H), 3.62 (s, 3H),1.78 (d, 3H).

Example 8 Preparation of (R)-2-(5-hydroxy-indol-1-yl)-propionic acidmethyl ester

A suspension of (R)-2-(5-benzyloxy-indol-1-yl)-propionic acid (Example4, 18.0 g, 0.061 mol), sodium bicarbonate (15.36 g, 0.183 mol), andiodomethane (11.40 mL, 0.183 mol) in DMF (164 mL) was stirred at rt for20 h. The reaction was monitored by reverse phase HPLC. Upon completion,the reaction was quenched by pouring into ice/water (300 mL) followed byextracting with ethyl acetate (2×150 mL). The combined organic layer waswashed with water (2×150 mL) and brine (150 mL) and was dried overanhydrous sodium sulfate. Filtration and concentration to dryness gave acrude oil which was purified by silica gel chromatography using 10-35%ethyl acetate/hexanes to give 16.38 g (87%) of(R)-2-(5-benzyloxy-indol-1-yl)-propionic acid methyl ester as an oil.

¹H NMR (DMSO-d₆) δ 7.45 (d, 2H), 7.38 (m, 3H), 7.13 (m, 2H), 7.13 (s,1H), 6.82 (d, 1H), 6.38 (s, 1H), 5.41 (q, 1H), 5.08 (s, 2H), 3.60 (s,3H), 1.70 (d, 3H); LC/MS (+esi) m/z 310.2 (M+H)⁺, RT 3.47 min.

Reverse Phase HPLC conditions: Column: YMC-Pack ProC18 (AS-300), 50×4.6mm (I.D.), S-5 μm, 12 nm (No. 040506614); Mobile Phase: A: 0.1% TFA inWater; B: 0.1% TFA in acetonitrile; Gradient: 90-5% A (10-95% B) in 7min.; Flow rate: 4.0 mL/min; Detector (UV): 220 nm. Retention time forthe title compound: 3.98 min.

A mixture of (R)-2-(5-benzyloxy-indol-1-yl)-propionic acid methyl ester(20.0 g, 0.065 mol) and palladium hydroxide (2.0 g, wet 20% Pd oncarbon) in ethanol (340 mL) under argon was heated to 40° C. To thissuspension was slowly added a solution of ammonium formate (5.04 g,0.078 mol) in ethanol/water (110.5/9.6 mL). Fifteen percent (15%) of thesolution was added initially over a period of 40 minutes to ensure thatthe reaction had initiated (indicated by reverse phase HPLC). Theremaining solution was then slowly added over a period of 1.5 h. Thereaction was monitored by reverse phase HPLC. Upon completion, thereaction mixture was cooled to rt and filtered through a silica gel pad.The pad was washed with ethanol. The combined fractions wereconcentrated to dryness under vacuum at 30° C. The crude product waspurified by silica gel chromatography using a gradient of 5-35% ethylacetate/hexanes to give 14.00 g (98%) of(R)-2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester as an oil.Chiral HPLC indicated an ee value of the desired enantiomer as 95%. ¹HNMR (400 MHz, DMSO-d₆) δ 8.70(s, 1H), 7.32 (s, 1H), 7.17 (d, 1H), 6.85(s, 1H), 6.61 (d, 1H), 6.28 (d, 1H), 5.32 (q, 1H), 3.60 (s, 3H), 1.70(d, 3H); LC/MS (+esi) m/z 220.1 (M+H)⁺, RT 2.07 min.

Chiral HPLC conditions for phenol: Column: Chiracel AD, 4.6 (I.D.)×250mm; Mobile Phase: A: 0.1% TFA in Hexanes; B: 0.1% TFA in IPA; Gradient:90-50% A (10-50% B) in 26 min; Flow rate: 1.0 mL/min; Detector (UV): 284nm. Retention time of the desired enantiomer: 20.45 min.

Reverse Phase HPLC conditions: Column: YMC-Pack ProC18 (AS-300), 50×4.6mm (I.D.), S-5 μm, 12 nm (No. 040506614); Mobile Phase: A: 0.1% TFA inWater; B: 0.1% TFA in Acetonitrile; Gradient: 90-5% A (10-95% B) in 7min; Flow rate: 4.0 mL/min; Detector (UV): 220 nm. Retention time of thetitle compound: 2.54 min.

Example 9 Preparation of methyl (5-hydroxy-1H-indol-1-yl)acetate

A solution of the compound prepared in Example 5 was treated asdescribed in Example 7. LC/MS m/z 206 (M+H)⁺, RT 1.68 min; ¹H NMR (400MHz, acetone-d₆) δ 6.98 (d, 1H), 6.95 (d, 1H), 6.92 (dd, 1H), 6.68 (dd,1H), 6.33 (dd, 1H), 4.72 (s, 2H), 4.68 (br s, 1H), 3.65 (s, 3H).

Step 1 Example 10 Preparation of1-(2-amino-4-methoxyphenyl)-2-chloroethanone

To 90 mL benzene cooled in an ice-water bath, was added 79.0 mL of a 1.0M solution of BCl₃ (79.0 mmol) in dichloromethane, followed by thedropwise addition of a solution of m-anisidine (8.84 g, 71.78 mmol) inbenzene (90 mL). To the resultant mixture was added chloroacetonitrile(6.50 g, 86.14 mmol), followed by AlCl₃ (10.53 g, 78.96 mmol). Thereaction mixture was heated at reflux under argon for 5 h resulting inthe formation of two layers. The reaction mixture was cooled to rt and200 mL ice-cold 2N HCl solution was added. A yellow precipitate formed.The mixture was heated at 90° C. until the precipitate dissolved overabout 1.5 h. The mixture was cooled to rt and extracted withdichloromethane and the organic layer was washed with water, dried overMgSO₄ and concentrated to yield a solid (9.93 g, 69%). ¹H NMR showedminor impurities. The material was used without further purification.LC/MS m/z 200 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (d, 1H), 7.34(bs, 2H), 6.23 (d, 1H), 6.11 (dd, 1H), 4.85 (s, 2H), 3.71 (s, 3H).

Step 2 Example 11 Preparation ofN-[2-(2-chloro-acetyl)-5-methoxy-phenyl]-acetamide

A solution of 1-(2-amino-4-methoxyphenyl)-2-chloroethanone (9.93 g,49.74 mmol) (Example 10) in acetic acid (100 mL) was heated at 85° C.for 4 h. The solvent was evaporated under reduced pressure to yield ayellow solid (12.00 g, 100%). LC/MS m/z 242 (M+H)⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 11.77 (s, 1H), 8.45 (d, 1H), 7.73 (d, 1H), 6.63 (dd, 1H),4.71 (s, 2H), 3.89 (s, 3H), 2.25 (s, 3H).

Step 3 Example 12 Preparation of1-acetyl-6-methoxy-1,2-dihydro-3H-indol-3-one

To a suspension of NaH (60% dispersion in mineral oil, 3.97 g, 99.3mmol) in DME (75 mL) was added an ice-cold solution ofN-[2-(chloroacetyl)-5-methoxyphenyl]acetamide (12.00 g, 49.7 mmol)(Example 11) in DME (165 mL) at 0° C. The mixture was stirred underargon for 15 minutes, then 2 N HCl (75 mL) solution was added slowly.The mixture was extracted with dichloromethane. The combined organiclayers were dried over MgSO₄ and concentrated to yield a solid. Thecrude material was purified on silica gel eluting with EtOAc/hexane(1:1) and then EtOAc to give a reddish solid (7.87 g, 77%) with minorimpurities: LC/MS m/z 206 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆)

7.94 (d, 1H), 7.59 (d, 1H), 6.80 (dd, 1H), 4.51 (s, 2H), 3.85 (s, 3H),2.24 (s, 3H).

Step 4 Example 13 Preparation of methyl(1-acetyl-6-methoxy-1H-indol-3-yl)acetate

A mixture of 1-acetyl-6-methoxy-1,2-dihydro-3H-indol-3-one (3.96 g, 19.3mmol) (Example 12) and methyl (triphenylphosphoranylidene)acetate (19.75g, 57.9 mmol) in toluene (60 mL) was heated at reflux under argon for 24h. The mixture was loaded on silica gel and eluted with EtOAc/hexane(1/5) to yield a thick oil (2.52 g, 50%). LC/MS m/z 262 (M+H)⁺; ¹H NMR(400 MHz, CDCl₃)

8.04 (br s, 1H), 7.38 (d, 1H), 7.31 (s, 1H), 6.92 (dd, 1H), 3.89 (s,3H), 3.74 (s, 3H), 3.71 (d, 2H), 2.62 (s, 3H).

Step 5 Example 14 Preparation of methyl(1-acetyl-6-hydroxy-1H-indol-3-yl)acetate

To a solution of methyl (1-acetyl-6-methoxy-1H-indol-3-yl)acetate (0.67g, 2.56 mmol) (Example 13) in dichloromethane (10 mL) was added 1 M BBr₃in dichloromethane (10.3 mL, 10.3 mmol) at −78° C. under argon. Stirringwas continued at −78° C. for 1 h, at 0° C. for 3 h and at rt for 18 hconsecutively. The reaction mixture was quenched with water anddichloromethane was added. Solid NaHCO₃ was added to adjust the pH ofthe mixture to 8. The mixture was extracted with CH₂Cl₂. The combinedorganic layers were dried over MgSO₄, filtered, and concentrated toyield a yellow solid (200.0 mg, 32%). LC/MS m/z 248 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆)

9.42 (s, 1H), 7.77 (d, 1H), 7.52 (s, 1H), 7.28 (d, 1H), 6.71 (dd, 1H),3.71 (s, 2H), 3.61 (s, 3H), 2.55 (s, 3H).

Step 1: Alkylation Example 15 Preparation of1,6-dibromo-2-(2-bromo-ethoxy)-naphthalene

1,6-Dibromo-2-naphthol (15.0 g, 49.67 mmol) and 1,2-dibromoethane (46.7g, 248.37 mmol) were added to a suspension of potassium carbonate (84.8g, 74.51 mmol) in acetonitrile (500 mL) at rt. The reaction mixture wasstirred for 48 h. Additional 1,2-dibromoethane (21.5 mL, 248.37 mmol)was added and the reaction mixture was stirred for 96 h at rt. Thereaction mixture was cooled to 0° C. with an ice bath and filteredthrough a fritted glass funnel. The resulting filtrate was concentratedunder reduced pressure to give the title compound (14.2 g, 69.9% yield)as a brown solid. GC/MS m/z 406 (M)⁺, RT 10.25 min; ¹H NMR (400 MHz,acetone-d₆) δ 14-8.09 (m, 2H), 7.96 (d, 1H), 7.71 (d, 1H), 7.54 (d, 1H),4.64-4.60 (m, 2H), 3.90-3.86 (m, 2H).

Example 16 Preparation of 1-(2-bromo-ethoxy)-2-chloro-4-methyl-benzene

To a solution of 2-chloro-4-methylphenol (500 mg, 3.62 mmol) inacetonitrile (20 mL) was added 1,2-dibromoethane (3.29 g, 17.53 mmol)followed by cesium carbonate (2.28 g, 7.01 mmol). The resulting mixturewas heated at 85° C. for 48 h, then cooled to rt. The solution wasfiltered through a Celite® pad. The Celite® was washed with acetone andthe combined eluents were concentrated under reduced pressure to givethe title compound as a white solid (697 mg, 76%). GC/MS (EI) m/z 248(M)⁺, RT 7.33 min.

Example 17 Preparation of 4-bromo-1-(2-bromo-ethoxy)-2-chloro-benzene

Using 4-bromo-2-chlorophenol as starting material, the title compoundwas prepared in a similar fashion as described in Example 16 to give awhite solid (612 mg, 77%). GC/MS (EI) m/z 312 (M⁺), RT 8.11 min.

Example 18 Preparation of 2-(2-bromo-ethoxy)-5-methoxy-benzonitrile

Using 2-cyano-4-methoxyphenol as starting material, the title compoundwas prepared in a similar fashion as described in Example 16 to give awhite solid (837 mg, 93%) GC/MS (EI) m/z 255 (M)⁺, RT 4.49 min.

Example 19 Preparation of 1-(2-bromo-ethoxy)-2-methoxy-4-methyl-benzene

To a solution of 2-methoxy-4-methylphenol (1000 mg, 7.24 mmol) in DMF(40 mL) at rt was added sodium hydride (60% dispersion in mineral oil,579 mg, 14.48 mmol). The reaction mixture was stirred for 1 h, then1,2-dibromoethane (6.80 g, 136.18 mmol) was added. The resultingsolution was heated at 50° C. for 24 h, then cooled to rt. The solutionwas treated with 2N HCl and extracted with EtOAc. The combined extractswere dried over MgSO₄, filtered, and concentrated under reducedpressure. The crude material was purified by silica gel chromatographyusing a step gradient of 30 and 50% EtOAc/hexanes to give the titlecompound as a white solid (460 mg, 24%). GC/MS (EI) m/z 244 (M)⁺, RT7.40 min.

Example 20 Preparation of 1-(2-bromo-ethoxy)-4-ethyl-2-methoxy-benzene

Using 4-ethyl-2-methoxyphenol as starting material, the title compoundwas prepared as described in Example 19 to give a white solid (371 mg,20%). GC/MS (EI) m/z 258 (M)⁺, RT 7.72 min.

Example 21 Preparation of 1-(2-bromo-ethoxy)-2-chloro-4-methoxy-benzene

Using 2-chloro-4-methoxyphenol as starting material, the title compoundwas prepared as described in Example 19 to give a white solid (744 mg,84%). GC/MS (EI) m/z 264 (M)⁺, RT 7.94 min.

Example 22 Preparation of 1-(3-bromo-propoxy)-2-methoxy-4-methyl-benzene

To a solution of 2-methoxy-4-methylphenol (500 mg, 3.62 mmol) inacetonitrile (20 mL) was added 1,3-dibromopropane (3.65 g, 201.89 mmol)followed by cesium carbonate (2.35 g, 7.24 mmol). The resulting solutionwas heated at 85° C. for 48 h, then cooled to rt. The solution wasfiltered through a Celite® pad. The Celite® was washed with acetone, andthe combined filtrates were concentrated under reduced pressure to givethe title compound as a white solid (395 mg, 42%). GC/MS (EI) m/z 258(M)⁺, RT 7.94 min.

Steps 2 and 3: Coupling and Hydrolysis Example 23 Preparation of (R) and(S)-2-{5-[2-(1,6-dibromo-naphthalen-2-yloxy)-ethoxy]-indol-1-yl}-propionicacid

To a solution of 1,6-dibromo-2-(2-bromo-ethoxy)naphthalene (0.4 g, 0.98mmol) (Example 15) in dry DMF (6 mL) was added2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester (0.215 g, 0.98mmol) (Example Z) followed by cesium carbonate (1.59 g, 4.9 mmol). Thereaction mixture was heated to 140° C. for 10 minutes and subsequentlyat 50° C. for 16 h. A saturated aqueous NaHCO₃ solution was added andthe reaction mixture was extracted with ethyl acetate. The combinedorganic layers were dried over MgSO₄, filtered, and concentrated. Thecrude material was purified on reverse phase HPLC with gradient of 40%to 100% of acetonitrile and water mixture. The racemic mixture of thetitle compounds (122 mg, 46.3%) was collected as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 7.23-7.22(1H, m), 8.00-7.97 (2H, m), 7.71 (1H, dd),7.63 (1H, d), 7.38 (1H, d), 7.29 (1H, d), 7.12 (1H, d), 6.79 (1H, dd),6.36 (1H, d), 5.24 (1H, q), 4.58-4.55 (2H, m), 4.37-4.34 (2H, m), 1.68(3H, d). LC/MS m/z 530 (M−H)⁻, RT 3.60 min

The racemic mixture (115 mg, 0.215 mmol) was separated into its twoenantiomers, designated, 23A and 23B, on a Chiral Pak AD 20×250 columneluting with an isocratic solvent system of 35% isopropanol (containing0.1% TFA) in hexanes (containing 0.1% TFA) at a flow rate of 20mL/minute. The first peak off the column (RT=9.1 min) was designatedExample 23A: (42 mg). ¹H NMR (400 MHz, acetone-d₆) δ 8.13-8.09 (m, 2H),7.95 (d, 1H), 7.70 (d, 1H), 7.62 (d, 1H), 7.38-7.33 (m, 2H), 7.19 (s,1H), 6.89-6.87 (m, 1H), 6.42 (s, 1H), 5.29 (q, 1H), 4.64-4:62 (m, 2H),4.47-4.45 (m, 2H), 1.80 (d, 3H). LC/MS m/z 531.9 (M+H)⁺, RT 3.85 min.The second peak off the column (RT=13.0 min) was designated Example 23B:40 mg. ¹H NMR (400 MHz, acetone-d₆) δ 8.15-8.11 (m, 2H), 7.97 (d, 1H),7.71 (d, 1H), 7.64 (d, 1H), 7.38-7.33 (m, 2H), 7.19 (s, 1H), 6.89-6.87(m, 1H), 6.42 (s, 1H), 5.30 (q, 1H), 4.66-4.64 (m, 2H), 4.48-4.46 (m,2H), 1.81 (d, 3H). LC/MS m/z 531.9 (M+H)⁺, RT 3.85 min.

Example 24 Preparation of2-{5-[2-(4-ethyl-2-methoxy-phenoxy)-ethoxy]-indol-1-yl}-propionic acid

To a solution of the compound from Example 20 (0.2 g, 0.77 mmol) in dryDMF (5 mL) was added 2-(5-hydroxy-indol-1-yl)-propionic acid methylester (Example 7, 0.169 g, 0.77 mmol) followed by cesium carbonate (0.5g, 1.54 mmol). The reaction mixture was heated to 140° C. for 3 h. HCl(2N) was added to the reaction mixture to adjust the pH to 2. Thereaction mixture was extracted with ethyl acetate. The combined organiclayers were dried over MgSO₄, filtered, and concentrated. The crudematerial was purified on reverse phase HPLC with gradient of 40% to 100%of acetonitrile and water mixture. The title compound (25 mg, 8%) wascollected as a brownish solid. ¹H NMR (400 MHz, acetone-d₆) δ 7.53 (s,1H), 7.42 (d, 1H), 7.01 (d, 1H), 6.97-6.93 (m, 2H), 6.84 (d, 2H), 6.71(dd, 1H), 5.37 (q, 1H), 4.42-4.29 (m, 4H), 3.81 (s, 3H), 2.58 (q, 2H),1.85 (d, 3H), 1.20 (t, 3H). LC/MS m/z 384.3 (M+H)⁺, RT 3.27 min.

Example 25 Preparation of2-{5-[2-(2-methoxy-4-methyl-phenoxy)-ethoxy]-indol-1-yl}-propionic acid

Using the compound from Example 19 as starting material the titlecompound was prepared as described in Example 24 to give a brownishsolid (45 mg, 14%). ¹H NMR (400 MHz, acetone-d₈) δ 7.32-7.27 (m, 2H),7.10 (d, 1H), 6.86-6.80 (m, 2H), 6.75 (s, 1H), 6.62 (d, 1H), 6.36 (d,1H), 5.23 (q, 1H), 4.29-4.25 (m, 4H), 3.74 (s, 3H), 2.22 (s, 3H), 1.75(d, 3H). LC/MS m/z 370.3 (M+H)⁺, RT 3.11 min.

Example 26 Preparation of2-{5-[2-(2-chloro-4-methyl-phenoxy)-ethoxy]-indol-1-yl}-propionic acid

Using the compound from Example 16 as starting material the titlecompound was prepared as described in Example 24 to give a brownishsolid (45 mg, 14%). ¹H NMR (400 MHz, acetone-d₆) δ7.32-7.27 (m, 2H),7.17 (s, 1H), 7.13 (d, 1H), 7.10 (d, 2H), 6.81 (dd, 1H), 6.37 (d, 1H),5.23 (q, 1H), 4.29-4.25 (m, 4H), 2.22 (s, 3H), 1.75 (d, 3H). LC/MS m/z374.1 (M+H)⁺, RT 3.37 min.

Example 27 Preparation of2-{5-[2-(4-bromo-2-chloro-phenoxy)-ethoxy]-indol-1-yl}-propionic acid

Using the compound from Example 17 as starting material, the titlecompound was prepared as described in Example 24 to give a brownishsolid (45 mg, 14%). ¹H NMR (400 MHz, acetone-d₆) δ 7.51 (d, 1H), 7.40(dd, 1H), 7.32-7.27 (m, 2H), 7.15-7.10 (m, 2H), 6.80 (dd, 1H), 6.35 (d,1H), 5.24 (q, 1H), 4.43-4.34 (m, 4H), 1.75 (d, 3H). LC/MS m/z 439.9(M+H)⁺, RT 3.54 min.

Example 28 Preparation of2-{5-[2-(2-chloro-4-methoxy-phenoxy)-ethoxy]-indol-1-yl}-propionic acid

Using the compound from Example 21 as starting material, the titlecompound was prepared as described in Example 24 to give a brownishsolid (32 mg, 10%). ¹H NMR (400 MHz, acetone-d₆) δ 7.38 (d, 1H), 7.34(d, 1H), 7.17-7.14 (m, 2H), 6.99 (d, 1H), 6.88 (dt, 2H), 6.42 (d, 1H),5.30 (q, 1H), 4.40-4.37 (m, 4H), 3.78 (s, 3H), 1.81 (d, 3H). LC/MS m/z390.1 (M+H)⁺, RT 3.18 min.

Example 29 Preparation of2-{5-[2-(2-cyano-4-methoxy-phenoxy)-ethoxy]-indol-1-yl}-propionic acid

Using the compound from Example 18 as starting material, the titlecompound was prepared as described in Example 24 to give a brownish oil(20 mg, 6%). ¹H NMR (400 MHz, acetone-d₆): δ 7.37 (d, 1H), 7.34 (d, 1H),7.29-7.17 (m, 4H), 6.86 (dd, 1H), 6.42 (d, 1H), 5.30 (q, 1H), 4.50-4.48(m, 2H), 4.41-4.39 (m, 2H), 3.83 (s, 3H), 1.81 (d, 3H). LC/MS m/z 381.1(M+H)⁺, RT 2.93 min.

Example 30 Preparation of2-{5-[3-(2-methoxy-4-methyl-phenoxy)-propoxy]-indol-1-yl}-propionic acid

Using the compound from Example 19 as starting material the titlecompound was prepared as described in Example 24 to give a brownishsolid (36 mg, 12%). ¹H NMR (400 MHz, acetone-d₆): δ 7.35 (d, 1H), 7.31(d, 1H), 7.11 (d, 1H), 6.85 (d, 1H), 6.82 (dd, 1H), 6.77 (s, 1H),6.67-6.65 (m, 1H), 6.40 (d, 1H), 5.27 (q, 1H), 4.21 (t, 2H), 4.16 (t,2H), 3.78 (s, 3H), 2.26 (s, 3H), 2.23 (t, 2H), 1.80 (d, 3H). LC/MS m/z384.1(M+H)⁺, RT 3.22 min.

Step 1: Alkylation Example 31 Preparation of 4-(allyloxy)benzonitrile

4-Hydroxybenzonitrile (30.0 g, 251.8 mmol), allyl bromide (39.6 g, 327.4mmol), and cesium carbonate (98.5 g, 302.2 mmol) were dissolved in DMF(900 mL), and 1 mL water was added. After stirring for 12 h at ambienttemperature, most of the DMF was removed in vacuo. Water was added andthe reaction mixture was extracted with ethyl acetate. The combinedorganic layers were washed with H₂O and brine. The organic layer wasdried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Thetitle compound was obtained as a white crystalline material (40 g,100%). ¹H NMR (400 MHz, CDCl₃) δ 4.60 (d, 2H), 5.34 (d, 1H), 5.43 (d,1H), 6.03 (m, 1H), 6.96 (d, 2H), 7.58 (d, 2H).

Step 2: Claisen Rearrangement Example 32 Preparation of3-allyl-4-hydroxybenzonitrile

4-(Allyloxy)benzonitrile (40.0 g, 251.3 mmol) (Example 31) was heatedunder argon at 200° C. for 20 h. After cooling to rt, the product waspurified via silica gel flash chromatography (ethyl acetate/hexane(v/v)=1:10 to 1:4) to give the title compound (27.5 g, 69%) as a whitecrystalline solid. ¹H NMR (400 MHz, CDCl₃) δ 3.44 (d, 2H), 5.18 (d, 1H),5.24 (d, 1H), 5.99 (m, 1H), 6.05 (br, 1H), 6.89 (d, 1H), 7.46 (d, 2H).

Step 3: Reduction Example 33 Preparation of4-hydroxy-3-propylbenzonitrile

3-Allyl-4-hydroxybenzonitrile (20.0 g, 126 mmol) (Example 32) wasdissolved in EtOH (320 mL) under argon. Pd/C (80 mg, 10%, Fluka) wasadded and the reaction mixture was stirred under a hydrogen atmosphere(1 atm) at rt for 20 h. The catalyst was filtered off, and then thereaction mixture was concentrated under reduced pressure, yielding 20.2g (99%) of the title compound as a slightly greenish oil. ¹H NMR (400MHz, CDCl₃): δ0.95 (t, 3H), 1.63 (m, 2H), 2.56 (m, 2H), 6.86 (d, 1H),7.30 (m, 2H).

Step 4: Thioamide Formation Example 34 Preparation of4-hydroxy-3-propylbenzenecarbothioamide

A solution of 4-hydroxy-3-propylbenzonitrile (35.63 g, 0.221 mol)(Example 33) in DMF (300 mL) was saturated with hydrogen sulfide at rt(moderate flow over 45 minutes). Temperature was monitored (increase ofabout 7° C.). To the solution was added diethylamine (45.73 mL, 0.442mol). The temperature increased by 10° C., and the green reactionmixture became darker green. Hydrogen sulfide was passed into the darkgreen solution for another 30 minutes (at this point the reactiontemperature was 40° C.). The reaction mixture was warmed to 60° C.Hydrogen sulfide was again passed into the solution at 60° C. over 2 h.The reaction mixture was cooled and stirred at rt for 54 h and most ofthe solvent removed under reduced pressure. The resultant residue waspartitioned between ethyl acetate (300 mL) and water (200 mL). Theorganic layer was washed with water (4×100 mL), then brine, and driedover sodium sulfate, filtered, and concentrated. The resultant orangeoil was triturated in hexanes (300 mL) and ether (25 mL) to give ayellow solid (39.97 g, 93%) after drying for 1 h under suction. LC/MSm/z 196.1 (M+H)⁺, RT 2.16 min. ¹H NMR (400 MHz, DMSO-d₆) δ 9.94 (s, 1H),9.44 (s, 1H), 9.14 (s, 1H), 7.73-7.65 (m, 2H), 6.73 (d, 1H), 2.51-2.47(m, 2H), 1.59-1.50 (m, 2H), 0.90 (t, 3H).

Example 35 Preparation of 4-hydroxy-3-methoxybenzenecarbothioamide

A solution of 4-hydroxy-3-methoxybenzonitrile (15.0 g, 0.1 mol) in DMF(150 mL) was treated with a slow flow of gaseous hydrogen sulfide for 30minutes at rt. Diethyl amine (15.6 mL, 11.0 g, 0.15 mol) was added andthe solution was heated at 70° C. for 4 h. The solution was cooled to rtand the residual H₂S was removed by passing argon through the solutionfor 30 minutes. The solvent was evaporated under reduced pressure andthe residue was filtered through a plug of silica, followed by washingwith EtOAc. Removal of the solvent resulted in a crude brown oil, whichwas used in the next step without further purification.

Step 5: Thiazole Formation Example 36 Preparation of2-propyl-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenol

A suspension of 4-hydroxy-3-propyl-thiobenzamide (5 g, 0.026 mol)(Example 34), 2-chlorocyclohexanone (4.07 g, 0.031 mol), andp-toluenesulfonic acid monohydrate (0.244 g, 1.28 mmol) in anhydroustoluene (100 mL) was heated to reflux in a Dean-Stark apparatus underargon for 12 h. At about 90° C., the mixture became a red orange oil andafter 4 h of refluxing, precipitation was observed. The reaction mixturewas cooled and diluted with ethyl acetate (50 mL). The organic layer waswashed successively with saturated sodium bicarbonate (2×50 mL), water(2×50 mL), brine, dried over sodium sulfate, and concentrated to givethe desired product as a tan solid (6.89 g, 98%). LC/MS m/z 274.3(M+H)⁺, RT 2.99 min. ¹H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 7.53-7.44(m, 2H), 6.81 (d, 1H), 2.72-2.68 (m, 4H), 2.54-2.49 (m, 2H), 1.78 (b,4H), 1.58-1.53 (m, 2H), 0.90 (t, 3H).

Example 37 Preparation of4-(4-isopropoxy-1,3-thiazol-2-yl)-2-methoxyphenol

4-Hydroxy-3-methoxybenzenecarbothioamide (3.0 g, 16.37 mmol) (Example35) and 2-chloro-N,N-dimethylacetamide were dissolved in isopropanol,and the mixture was heated at reflux for 12 h. The solvent was removedunder reduced pressure. The residue was washed with water and extractedwith ethyl acetate. The combined organic layers were dried over Na₂SO₄,filtered, and the solvent was removed in vacuo. Purification via silicagel flash chromatography (ethyl acetate/hexane (v/v)=1:4) yielded asolid (1.99 g, 46%). ¹H NMR (400 MHz, CDCl₃) δ 1.42 (d, 6H), 3.91 (s,3H), 4.64 (septet, 1H), 5.95 (s, 1H), 6.0 (br, 1H), 6.91 (d, 1H), 7.36(d, 1H), 7.53 (s, 1H).

When R⁶=n-propyl, the cyanophenol was prepared based on examplesdescribed in Method 4.

Step 1: Hydrolysis of Nitrile Example 38 Preparation of4-hydroxy-3-methoxy-benzamide

A 3% aqueous solution of hydrogen peroxide (155 mL, 0.151 mol) was addedto a flask containing 4-hydroxy-3-methoxybenzonitrile (5.00 g, 33.52mmol) at rt. Solid KOH (9.78 g, 174.33 mmol) was added slowly. Gas wasevolved and the temperature of the rose. The solution was stirred for 16h, and excess sodium sulfite was added. The mixture was then filteredand the solution was acidified to pH 2 with 2N HCl. The aqueous solutionwas extracted with dichloromethane. The combined organic layers weredried over MgSO₄, filtered, and concentrated to give the product as apale yellow solid (4.27 g, 76.2%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s,1H), 7.75 (s, 1H), 7.42 (d, 1H), 7.34 (dd, 1H), 7.096 (s, 1H), 6.76 (d,1H), 3.78 (s, 3H).

Step 2: Oxazole Formation Example 39 Preparation of4-(4-ethyl-1,3-oxazol-2-yl)-2-methoxyphenol

To a solution of 4-hydroxy-3-methoxybenzamide (460 mg, 2.75 mmol)(Example 38) in toluene (3 mL)/1,4-dioxane (3 mL), was added1-bromo-2-butanone (623.29 mg, 4.13 mmol). The solution was heated toreflux for 18 h. The reaction mixture was cooled to rt, and the solventwas removed under reduced pressure. The crude residue was purified onsilica gel to give the title compound as a yellow oil (434 mg, 72%). ¹HNMR (400 MHz, DMSO-d₆) δ 9.60 (s, 1H), 7.78 (s, 1H), 7.39 (d, 1H), 7.36(dd, 1H), 6.83 (d, 1H), 3.79 (s, 3H), 2.45 (m, 2H), 1.18 (t, 3H).

Steps 4 and 5 were also used during the synthesis of targets where then-propyl group was replaced with H and MeO groups.

Step 1: Allylation Example 40 Preparation of benzyl 4-(allyloxy)benzoate

To a solution of benzyl 4-hydroxybenzoate (15.00 g, 65.1 mmol) in 130 mLacetone cooled in an ice water bath was added allyl bromide (11.4 mL,130.1 mmol), followed by portionwise addition of potassium carbonate(45.00 g, 325.3 mmol). The ice bath was removed and the reaction mixturewas warmed to rt. The mixture was stirred for 19 h. The precipitateswere removed by filtration and the filtrate was concentrated to yield acolorless oil (17.65 g, 100%). LC/MS m/z 269 (M+H)⁺; ¹H NMR (400 MHz,CDCl₃) δ 8.00-8.04 (m, 2H), 7.31-7.45 (m, 5H), 6.91-6.94 (m, 2H),6.00-6.91 (m, 1H), 5.30-5.45 (m, 4H), 4.58-4.61 (m, 2H).

Step 2: Claisen Rearrangement Example 41 Preparation of benzyl3-allyl-4-hydroxybenzoate

Benzyl 4-(allyloxy)benzoate (15.50 g, 57.8 mmol) (Example 40) was heatedat 200° C. under argon for 18 h with stirring. Benzyl3-allyl-4-hydroxybenzoate was obtained as a solid (15.40 g, 99%). LC/MSm/z 269 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) 37.86-7.89 (m, 2H), 7.33-7.45(m, 5H), 6.83 (d, 1H), 5.96-6.06 (m, 1H), 5.48 (s, 1H), 5.33 (s, 2H),5.15-5.20 (m, 2H), 3.45 (d, 2H).

Step 3: Reduction Example 42 Preparation of 4-hydroxy-3-propylbenzoicacid

A mixture of benzyl 3-allyl-4-hydroxybenzoate (15.40 g, 57.4 mmol)(Example 41), 10% Pd/C (1.54 g), and 60 mL ethanol was placed in a Parrhydrogenator under 60 psi of H₂. The mixture was shaken for 2 h. Thecatalyst was removed by filtering through a plug of Celite®. Thefiltrate was concentrated to yield a thick oil (10.5 g 100%). ¹H NMR(400 MHz, DMSO-d₆) δ 12.36 (br s, 1H), 10.08 (s, 1H), 7.59-7.63 (m, 2H),6.81 (d, 1H), 2.49-2.53 (m, 2H), 1.50-1.59 (m, 2H), 0.89 (t, 3H).

Step 4: Amidation Example 43 Preparation of 4-hydroxy-3-propyl-benzamide

A solution of 4-hydroxy-3-propylbenzoic acid (7.30 g, 40.5 mmol)(Example 42) in thionyl chloride (15 mL, 205.6 mmol) was heated atreflux for 2 h and concentrated under reduced pressure. The residue wasdissolved in THF. This solution was added to aqueous 30% NH₄OH solution(30 mL) at 0° C. The reaction mixture was stirred for 20 h at rt. Thecrude material was purified on HPLC to yield a solid (0.82 g, 11%).LC/MS m/z 180 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 7.66 (brs, 1H), 7.51-7.59 (m, 2H), 7.01 (br, s, 1H), 6.75 (d, 1H), 2.47-2.51 (m,2H), 1.51-1.60 (m, 2H), 0.90 (t, 3H).

Step 5: Oxazole Formation Example 44 Preparation of4-(4-ethyl-1,3-oxazol-2-yl)-2-propyl-phenol

A mixture of 4-hydroxy-3-propylbenzamide (200.0 mg, 1.1 mmol) (Example43), 1-bromo-2-butanone (0.19 mL, 1.7 mmol), toluene (1.5 mL), and1,4-dioxane (1.5 mL) was heated at reflux for 8 h with a Dean-Starktrap. The solvents were evaporated. The crude product was purified onHPLC to yield a solid (124.2 mg, 48%). LC/MS m/z 232 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ 9.87 (s, 1H), 7.56-7.76 (m, 3H), 6.85 (d, J=8.4 Hz, 1H),2.46-2.56 (m, 4H), 1.52-1.61 (m, 2H), 1.18 (t, J=7.6 Hz, 3H), 0.91 (t,J=7.3 Hz, 3H).

Step 1: Dehydration Example 45 Preparation of7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-ol

1-(2,4-Dihydroxy-3-propylphenyl)-2,2,2-trifluoroethanone oxime (preparedby the method described in WO 97/28137, 4.2 g, 15.96 mmol) andtriphenylphosphine (8.82 g, 33.6 mmol) were dissolved in THF (250 mL)and the mixture was cooled to 0° C. A solution of diethylazodicarboxylate (5.02 mL, 32.0 mmol) in THF (150 mL) was then slowlyadded over a period of 30 minutes. The reaction mixture was stirred for1 h at 0° C. After addition of water (500 mL), the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith brine and dried over sodium sulfate. The solvent was removed invacuo and the product purified via silica gel flash chromatography(ethyl acetate/hexane (v/v)=1:6). The product was obtained as awhite-yellow powder in a yield of 1.96 g (8.0 mmol, 50%). ¹H NMR (300MHz, CDCl₃) δ 1.00 (t, 3H), 1.73 (m, 2H), 2.88 (t, 2H), 5.34 (s, 1H),6.93 (d, 1H), 7.48 (d, 1H).

Step 2: Alkylation Example 46 Preparation of6-(3-bromo-propoxy)-7-propyl-3-trifluoromethyl-1,2-benzo[d]-isoxazole

To a mixture of 7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-ol (3.53g, 14.4 mmol) (Example 45) and cesium carbonate (5.63 g, 17.3 mmol) inDMF (12 mL, containing 1% v/v of water), was added 1,3-dibromopropane(14.5 g, 72.0 mmol). The reaction mixture was stirred for 12 h at rt andthe solvents were removed under reduced pressure. The residue waspurified by silica gel flash chromatography (100% hexanes, then 2-5%EtOAc in hexanes) to give the product as a colorless oil (2.4 g, 46%).¹H NMR (300 MHz, CDCl₃) δ 7.58 (d, 1H), 7.09 (d, 1H), 4.25 (t, 2H), 3.64(t, 2H), 2.92 (t, 2H), 2.40 (m, 2H), 1.72 (m, 2H), 0.99 (t, 3H).

Step 1: Alkylation Example 47 Preparation of methyl[5-(3-bromopropoxy)-1H-indol-1-yl]acetate

To a solution of methyl (5-hydroxy-1H-indol-1-yl)acetate (1.0 g, 4.87mmol) (Example 9) in 35 mL DMF, was added 1,3-dibromopropane (5.90 g,29.24 mmol) and Cs₂CO₃ (3.18 g, 9.75 mmol). The mixture was stirred atrt for 6 h, and then the solvent was evaporated under reduced pressure.The residue was suspended in EtOAc, filtered, and the filter cake waswashed with EtOAc. The combined organic layers were dried, concentrated,and purified by column chromatography (0-10% EtOAc in hexane) to give720 mg (45%) of the product containing minor impurities. This materialwas used in later steps with no further purification. ¹H NMR (400 MHz,CDCl₃) δ 7.18-7.10 (m, 2H), 7.05 (d, 1H), 6.94-6.85 (m, 1H), 6.50 (d,1H), 4.80 (s, 2H), 4.18 (t, 2H), 3.75 (s, 3H), 3.65 (t, 2H), 2.40-2.30(m, 2H).

Example 48 Preparation of 2-[5-(3-bromo-propoxy)-indol-1-yl]-propionicacid methyl ester

The title compound was prepared according to the method described inExample 47. ¹H NMR (400 MHz, CD₃OD) δ 1.82 (d 3H), 2.34 (m 2H), 3.64 (t2H), 3.70 (s 3H), 4.14 (t 2H), 5.1 (q 1H), 6.48 (d 1H), 6.85-6.90 (m1H), 7.11 (d 1H), 7.18-7.25 (m 2H).

Example 49 Preparation of[5-(3-bromo-propoxy)-3-methyl-indo-1-yl]-acetic acid ethyl ester

The title compound was prepared according to the method described inExample 47. ¹H NMR (400 MHz, CDCl₃) δ 7.10 (m, 1H), 7.02 (d, 1H),6.82-6.85 (m, 2H), 4.77 (s, 2H), 4.18 (m, 4H), 3.62 (t, 2H), 2.39 (m,2H), 2.31 (s, 3H), 1.23 (t, 3H).

Example 50 Preparation of2-[5-(3-bromo-propoxy)-3-methyl-indol-1-yl]-propionic acid methyl ester

The title compound was prepared according to the method described inExample 47. ¹H NMR (400 MHz, CDCl₃) δ 7.18 (d, 1H), 7.01 (m, 2H), 6.82(m, 1H), 5.02 (q, 1H), 4.19 (t, 2H), 3.70 (s, 3H), 3.63 (t, 2H), 2.39(m, 2H), 2.30 (s, 3H), 1.79 (d, 3H).

Step 2: Coupling Example 51 Preparation of methyl{5-[3-(4-cyano-2-propylphenoxy)propoxy]-1H-indol-1-yl}acetate

To a mixture of 4-hydroxy-3-propylbenzonitrile (Example 33, 1.33 g, 8.28mmol) and methyl [5-(3-bromopropoxy)-1H-indol-1-yl]acetate (Example 47,2.70 g, 8.28 mmol) in DMF (50 mL, containing 1% water), was added cesiumcarbonate (5.39 g, 16.55 mmol). The mixture was stirred at rt for 24 hand then the solvent was evaporated under reduced pressure. The residuewas suspended in ethyl acetate and filtered. The filtrate wasconcentrated and purified via silica gel column chromatography (0-10%EtOAc in hexanes) to give 787 mg (23%) of the product as a solid. Thiswas used in later steps with no further purification.

Step 3: Thioamide Formation Example 52 Preparation of methyl(5-{3-[4-(aminocarbonothioyl)-2-propylphenoxy]-propoxy}-1H-indol-1-yl)acetate

Hydrogen sulfide was passed through a solution of methyl{5-[3-(4-cyano-2-propylphenoxy)propoxy]-1H-indol-1-yl}acetate (Example51, 787 mg, 1.94 mmol) in DMF (15 mL) for 30 minutes at rt. Diethylamine (0.3 mL, 2.90 mmol) was added, and the solution was heated to 70°C. for 3 h. The reaction mixture was cooled to rt, and the residual H₂Swas removed by passing argon through the reaction mixture for 30minutes. The solvent was evaporated under reduced pressure and theresidue was filtered through a plug of silica and washed with EtOAc.Concentration of solvent yielded a brown oil which was used in the nextstep without further purification. LC/MS m/z 441.2 (M+H)⁺; RT 3.35 min.

Step 4: Thiazole Formation Example 53 Preparation of methyl(5-{3-[4-(4-ethyl-1,3-thiazol-2-yl)-2-propylphenoxy]propoxy}-1H-indol-1-yl)acetate

To a solution of methyl(5-{3-[4-(aminocarbonothioyl)-2-propyl-phenoxy]-propoxy}-1H-indol-1-yl)acetate(Example 52, 500 mg, 1.14 mmol) in ethanol (35 mL), was added1-bromo-2-butanone (739 mg, 2.27 mmol) and pyridine (0.14 mL, 135 mg,1.70 mmol). The reaction mixture was stirred for 3 h at 70° C. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel chromatography (0-15% EtOAc in hexane) to give 89mg (16%) of the title compound. ¹H NMR (400 MHz, CDCl₃) δ 7.75-7.70 (m,2H), 7.18-7.12 (m, 2H), 7.05 (d, 1H) 6.95-6.85 (m, 2H), 6.80 (s, 1H),6.48 (d, 1H), 4.85 (s, 2H), 4.25-4.20 (m, 4H), 3.75 (s, 3H), 2.85 (q,2H), 2.70-2.60 (m, 2H), 2.40-2.30 (m, 2H), 1.75-1.60 (m, 2H), 1.35 (t,3H), 0.95 (t, 3H).

Step 5: Hydrolysis Example 54 Preparation of(5-{3-[4-(4-ethyl-1,3-thiazol-2-yl)-2-propylphenoxy]propoxy}-1H-indol-1-yl)aceticacid

To a solution of methyl(5-{3-[4-(4-ethyl-1,3-thiazol-2-yl)-2-propylphenoxy]propoxy}-1H-indol-1-yl)acetate(Example 53, 89 mg, 0.18 mmol) in 3.0 mL THF, was added LiOH.H₂O (30 mg,0.72 mmol) in water (1.0 mL). The mixture was stirred for 12 h at rt.The solvents were evaporated and the residue was suspended in a smallvolume of water. The pH of the mixture was adjusted to 3 with 1 N HCl.The aqueous layer was extracted with ethyl acetate. The combined organiclayers were concentrated to give 65 mg (75%) of the product as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, 1H), 7.35 (dd, 1H), 7.10-7.05(m, 2H), 7.08 (d, 1H), 6.90 (dd, 1H), 6.78 (s, 1H), 6.45 (d, 1H), 6.35(d, 1H), 4.85 (s, 2H), 4.34 (t, 2H), 4.26 (t, 2H), 2.92 (q, 2H),2.55-2.45 (m, 2H), 2.25-2.15 (m, 2H), 1.62-1.50 (m, 2H), 1.35 (t, 3H),0.92 (t, 3H).

[5-(3-Bromo-propoxy)-indol-1-yl]-acetic acid methyl ester was preparedin similar fashion as described in Method 8.

Step 1: Coupling Example 55 Preparation of methyl(5-{3-[2-propyl-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)phenoxy]propoxy}-1H-indol-1-yl)acetate

2-Propyl-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenol (Example 36,0.75 g, 2.76 mmol) was combined with[5-(3-bromo-propoxy)-indol-1-yl]-acetic acid methyl ester (Example 47,0.75 g, 2.30 mmol) in 12 mL DMF (containing 1 v/v % of water). To thismixture was added Cs₂CO₃ (1.50 g, 4.60 mmol), and the resulting mixturewas allowed to stir at rt for 14 h. At this time, the reaction mixturewas diluted with EtOAc (50 mL) and then washed three times with water(75 mL total). The water layers were extracted with EtOAc (25 mL) andthe combined organic extracts were dried over MgSO₄, filtered, and thenconcentrated under reduced pressure. Purification via flash silica gelchromatography (1:1 hexane/EtOAc) gave the title compound (800 mg, 64%)as a white solid. ¹H NMR (400 MHz, CDCl₃) & 7.75-7.70 (m, 2H), 7.18-7.10(m, 2H), 7.05 (d, 1H), 6.92-6.85 (m, 2H), 6.48 (d, 1H), 4.84 (s, 2H),4.30-4.20 (m, 4H), 3.75 (s, 3H), 2.90-2.75 (m, 4H) 2.70-2.60 (m, 2H),2.40-2.30 (m, 2H), 1.95-1.85 (m, 4H), 1.70-1.58 (m, 2H), 0.95 (t, 3H).

Example 56 Preparation of methyl(5-{3-[4-(4-isopropoxy-1,3-thiazol-2-yl)-2-methoxyphenoxy]propoxy}-1H-indol-1-yl)acetate

To a mixture of 4-(4-isopropoxy-1,3-thiazol-2-yl)-2-methoxy-phenol(Example 37, 269 mg, 1.01 mmol) and ethyl[5-(3-bromopropoxy)-1H-indol-1-yl]acetate (Example 47, 331 mg, 1.01mmol) in 8 mL DMF (containing 1 v/v % of water), was added cesiumcarbonate (661 mg, 2.03 mmol). After stirring the reaction mixture for16 h at rt, DMF was evaporated under reduced pressure. The residue wassuspended in ethyl acetate and filtered through a silica gel plug togive 204 mg (39%) of a white solid, which was used in the next step withno further purification.

Step 2: Hydrolysis Example 57 Preparation of(5-{3-[2-propyl-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)phenoxy]propoxy}-1H-indol-1-yl)aceticacid

To a solution of methyl(5-{3-[2-propyl-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)phenoxy]propoxy}-1H-indol-1-yl)acetate(Example 55, 145 mg, 0.28 mmol) in THF (4.8 mL), was added LiOH.H₂O (39mg, 0.84 mmol) in water (1.6 mL), and the mixture was stirred for 12 hat rt. The solvents were evaporated and a small volume of water wasadded to the residue. The pH of the mixture was adjusted to 3 with 1NHCl. The aqueous layer was extracted with ethyl acetate. The combinedorganic layers were dried, filtered, and concentrated to give 140 mg(99%) of the product as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.30(d, 1H), 7.25-7.15 (m, 3H), 7.10 (d, 1H), 6.92 (dd, 1H), 6.45 (d, 1H),6.20 (d, 1H), 4.85 (s, 2H), 4.40-4.32 (m, 2H), 4.32-4.22 (m, 2H),2.90-2.80 (br, 2H), 2.80-2.70 (br, 2H), 2.50-2.40 (m, 2H), 2.25-2.05 (m,2H), 1.95-1.75 (br, 4H), 1.60-1.40 (m, 2H), 0.90 (t, 3H). LC/MS m/z505.2 (M+H)⁺, RT 3.88 min.

Example 58 Preparation of(5-{3-[4-(4-isopropoxy-1,3-thiazol-2-yl)-2-methoxyphenoxy]propoxy-1H-indol-1-yl)aceticacid

Methyl(5-{3-[4-(4-isopropoxy-1,3-thiazol-2-yl)-2-methoxyphenoxy]propoxy}-1H-indol-1-yl)acetate(Example 56, 204 mg, 0.40 mmol) was dissolved in THF (3 mL) in a roundbottom flask, and LiOH.H₂O (67 mg, 1.60 mmol) in water (1 mL) was added.The mixture was stirred at rt for 16 h. The solvents were evaporatedunder reduced pressure and the residue was suspended in small volume ofwater. The pH of the mixture was adjusted to 3 with 1N HCl. The aqueouslayer was immediately extracted with EtOAc. The combined organic layerswere dried, filtered, and concentrated to give 182 mg (91%) of theproduct as a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 7.42 (s, 1H), 7.32(d, 1H), 7.15-7.08 (m, 2H), 7.04 (d, 1H), 6.88 (dd, 1H), 6.82 (d, 1H),6.52 (d, 1H), 5.96 (s, 1H), 4.85 (s, 2H), 4.70-4.60 (q, 1H), 4.35-4.20(m, 4H), 3.88 (s, 3H), 2.38-2.28 (m, 2H), 1.42 (d, 6H).

Example 59 Preparation of(S)-2-(5-{3-[4-(4-ethoxy-5-methyl-thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-propionicacid and(R)-2-(5-{3-[4-(4-ethoxy-5-methyl-thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-propionicacid

The corresponding racemic ester (266 mg, 0.50 mmol) prepared accordingto the method described in Example 55 was dissolved in a mixture of3:3:1 THF, MeOH, and water (7 mL) and LiOH.H₂O (118 mg, 4.96 mmol) wasadded. The mixture was stirred at 50° C. for 3 h. The solvents wereevaporated under reduced pressure. The residue was acidified with 1 NHCl. The aqueous layer was immediately extracted with EtOAc. Thecombined organic layers were dried and concentrated. The crude productwas purified by reversed phase HPLC using a gradient of 20 to 100% A (A:CH₃CN 0.1% TFA; B: Water 0.1% TFA) to give a racemic mixture of thetitle compound as a white solid. ¹H NMR (400 MHz, acetone-d₆) δ7.67-7.65 (m, 2H), 7.35 (d, 1H), 7.32 (d, 1H), 7.12 (d, 1H), 7.02 (d,1H), 7.85 (dd, 1H), 6.41 (d, 1H), 5.28 (q, 1H), 4.37 (q, 2H), 4.29-4.23(m, 4H), 2.66 (t, 2H), 2.31 (t, 2H), 2.25 (s, 3H), 1.80 (d, 3H),1.68-1.62 (m, 2H), 1.36 (t, 3H), 0.96 (t, 3H). LC/MS m/z 523.1 (M+H)⁺;RT 4.46 min.

The racemic acid mixture (0.088 g) was resolved by chiral HPLC using aChiral Pak AD-H column eluting with a gradient of 10 to 20% of B (A:hexanes; B: isopropanol) over 20 minutes at a flow-rate of 15 mL/min. Awhite solid was obtained after concentrating the fractions correlatingto the first peak (26.5 mg, RT=14.4 min) designated as the Example 59A.¹H NMR (400 MHz, acetone-d₆) δ 7.68-7.64 (m, 2H), 7.36 (d, 1H), 7.32 (d,1H), 7.12 (d, 1H), 7.04 (d, 1H), 6.84 (dd, 1H), 6.40 (d, 1H), 5.28 (q,1H), 4.37 (q, 2H), 4.31-4.24 (m, 4H), 2.66 (t, 2H), 2.31 (t, 2H), 2.25(s, 3H), 1.80 (d, 3H), 1.68-1.62 (m, 2H), 1.36 (t, 3H), 0.96 (t, 3H)LC/MS m/z 523.3 (M+H)⁺; RT=4.47 min. The other enantiomer, designated asExample 59B, was collected from the fractions correlating to the secondpeak as a white solid (24.4 mg, RT=16.7 min). ¹H NMR (400 MHz, Acetoned₆) δ 7.68-7.64 (m, 2H), 7.36 (d, 1H), 7.32 (d, 1H), 7.12 (d, 1H), 7.04(d, 1H), 6.84 (dd, 1H), 6.40 (d, 1H), 5.28 (q, 1H), 4.37 (q, 2H),4.31-4.24 (m, 4H), 2.66 (t, 2H), 2.31 (t, 2H), 2.25 (s, 3H), 1.80 (d,3H), 1.68-1.62 (m, 2H), 1.36 (t, 3H), 0.96 (t, 3H). LC/MS m/z 523.3(M+H)⁺; RT 4.47 min.

Example 60 Preparation of(S)-2-(5-{3-[4-(4-ethoxy-5-methyl-thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-3-methyl-indol-1-yl)-propionicacid and(R)-2-(5-{3-[4-(4-ethoxy-5-methyl-thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-3-methyl-indol-1-yl)-propionicacid

The racemic acid mixture (0.119 g) prepared by the method of Example 59was resolved by chiral HPLC using a Chiral Pak AD column eluting with aisocratic system (10% isopropanol and 90% hexanes) for 20 minutes at aflow-rate of 15 mL/min. This yielded a white solid (39.8 mg) of thecompound, designated as Example 60A, corresponding to the first peak(RT=11.9 min). LC/MS m/z 537.3 (M+H)⁺; RT 4.60 min. The otherenantiomer, designated Example 60B, was collected as a white solidcorresponding to the second peak (38.1 mg, RT=14.5 min) LC/MS m/z 537.3(M+H)⁺; RT 4.60 min.

Example 61 Preparation of(S)-2-(5-{3-[4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-propionicacid and(R)-2-(5-{3-[4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-propionicacid

The corresponding racemic acid mixture (0.989 g) prepared according tothe method of Example 59 was resolved by chiral HPLC using a Pirklecovalent (R,R) whelk-02 chiral column 20×250 mm, eluting with anisocratic solvent system containing 20% B (A: hexanes; B: 1:1methanol/ethanol) over 20 minutes at a flow-rate of 25 mL/min. Thisyielded the compound, designated as Example 61A, as a white solid (182mg) corresponding to the first peak (RT=14.7 min). LC/MS m/z 477.2(M+H)⁺; RT 3.52 min. The other enantiomer, designated as Example 61B,was collected as a white solid (159 mg) correlating to the second peak(RT=16.2 min). LC/MS m/z 477.2 (M+H)⁺; RT 3.52 min.

Step 1: Coupling Example 62 Preparation of2-(5-{3-[4-(4-ethyl-oxazol-2-yl)-2-methoxy-phenoxy]-propoxy}-indol-1-yl)-propionicacid methyl ester

2-[5-(3-Bromo-propoxy)-indol-1-yl]-propionic acid methyl ester (Example48, 170.20 mg, 0.50 mmol) and 4-(4-ethyl-oxazol-2-yl)-2-methoxy-phenol(Example 39, 109.68 mg, 0.50 mmol) were dissolved in DMF (2 mL) at rt.Cesium carbonate (244.5 mg, 0.75 mmol) was added to the solution,followed by three drops of water. The mixture was stirred at rt for 17h. The crude reaction mixture was filtered and purified by HPLC. Thedesired product was isolated as a white solid (143.8 mg, 60.1%). LC/MSm/z 479.3 (M+H)⁺; RT 3.59 min. ¹H NMR (400 MHz, CD₂Cl₂) δ 7.58 (d, 1H),7.56 (s, 1H), 7.41 (m, 1H), 7.24 (d, 1H), 7.19 (d, 1H), 7.11 (d, 1H),7.00 (d, 1H), 6.88 (dd, 1H), 6.46 (d, 1H), 5.11 (q, 1H), 4.28 (t, 2H),4.22 (t, 2H), 3.93 (s, 3H), 3.71 (s, 3H), 2.61 (q, 2H), 2.34 (m, 2H),1.82 (d, 3H), 1.29 (t, 3H).

Step 2: Hydrolysis Example 63 Preparation of2-(5-{3-[4-(4-ethyl-oxazol-2-yl)-2-methoxy-phenoxy]-propoxy}-indol-1-yl)-propionicacid

2-(5-{3-[4-(4-Ethyl-oxazol-2-yl)-2-methoxy-phenoxy]-propoxy}-indol-1-yl)-propionicacid methyl ester (Example 62, 129.7 mg, 0.27 mmol) was dissolved in asolution of tetrahydrofuran (2 mL), methanol (1 mL), and water (2 mL).Lithium hydroxide (32.45 mg, 1.36 mmol) was added and the mixture wasstirred at rt for 2 h. The solution was concentrated, diluted with water(5 mL), and acidified with 1N HCl. The resulting white precipitate wascollected by filtration and dried to give the title compound (100.1 mg,79.5%). LC/MS m/z 465.1 (M+H)⁺; RT 3.25 min. ¹H NMR (400 MHz, DMSO-d₆) δ7.82 (s, 1H), 7.47 (dd, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 7.28 (d, 1H),7.11 (d, 1H), 7.06 (d, 1H), 6.77 (dd, 1H), 6.34 (d, 1H), 5.24 (q, 1H),4.19 (t, 2H), 4.12 (t, 2H), 3.82 (s, 3H), 2.52 (m, 2H), 2.20 (m, 2H),1.68 (d, 3H), 1.19 (t, 3H).

Similar conditions were used in the preparation of 3-indole and 1-indoleacetic acid derivatives.

Step 1: Coupling Example 64 Preparation of{1-acetyl-6-[3-(7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-yloyl)-propoxy]-1H-indol-3-yl}-aceticacid methyl ester

A mixture of (1-acetyl-6-hydroxy-1H-indol-3-yl)-acetic acid methyl ester(Example 14, 90.0 mg, 0.364 mmol),6-(3-bromo-propoxy)-7-propyl-3-trifluoromethyl-benzo[d]isoxazole(Example 46, 140.0 mg, 0.382 mmol), Cs₂CO₃ (124.5 mg, 0.382 mmol), andwater (3 drops) in DMF (3.6 mL) was stirred at rt under argon for 20 h.The reaction mixture was loaded on to silica gel and eluted withEtOAc/hexane (5:95) to yield the title compound as a white solid (110.0mg, 57%). LC/MS m/z 533 (M+H)⁺, RT 4.25 min; ¹H NMR (400 MHz, CDCl₃) δ8.08 (s, 1H), 6.92-7.57 (m, 5H), 4.26-4.35 (m, 4H), 3.73 (s, 3H), 3.70(s, 2H), 2.81-2.93 (m, 2H), 2.61 (s, 3H), 2.35-2.36 (m, 2H), 1.63-1.69(m, 2H), 0.93 (d, 3H).

Step 2: Hydrolysis Example 65 Preparation of(6-[3-(7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-yloxy)-6-propoxy]-1H-indol-3-yl}-aceticacid

To a solution of{1-acetyl-6-[3-(7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-yloyl)-propoxy]-1H-indol-3-yl}-aceticacid methyl ester (Example 64, 102.7 mg, 0.193 mmol) in THF (1 mL) wasadded 1.0 M LiOH solution (0.66 mL) in MeOH/water (1:1). The mixture washeated at 60° C. for 2 h. The solvents were evaporated under reducedpressure. Water was added to dissolve the residue. The pH of the mixturewas adjusted to 1-2 with concentrated HCl. The mixture was extractedwith dichloromethane (3×20 mL). The combined organic layers were driedover MgSO₄, filtered, and concentrated to yield the title compound as asolid (80.1 mg, 80%). LC/MS m/z 477 (M+H)⁺, RT 3.84 min; ¹H NMR (400MHz, DMSO-d₆) δ 12.08 (s, 1H), 10.67 (s, 1H), 6.63-7.75 (m, 6H), 4.35(t, 2H), 4.16 (t, 2H), 3.56 (s, 2H), 2.83-2.87 (m, 2H), 2.22-2.28 (m,2H), 1.57-1.66 (m, 2H), 0.87 (t, 3H).

Step 1: Propanediol Addition Example 66 Preparation of6-(3-hydroxypropoxy)nicotinonitrile

Sodium hydride (0.42 g, 60% suspension in mineral oil, 10.61 mmol) wasadded to a solution of 1,3-propanediol (2.30 mL, 31.83 mmol) in DMF (22mL) at 0° C., and the mixture was stirred at rt for 20 minutes. To theresultant pale yellow slurry was added 6-chloronicotinonitrile (1.50 g,10.61 mmol) in one portion. The mixture was stirred at rt for 18 h. Itwas then poured into water. The precipitates were filtered and thefiltrate was extracted with ethyl acetate. The organic extract waswashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure to give the title compound (1.56 g, 83%) as a whitesolid. ¹H NMR (300 MHz, CD₂Cl₂) δ 8.47 (d, 1H), 7.82-7.79 (m, 1H),6.84-6.82 (m, 1H), 4.53 (t, 2H), 3.75 (t, 2H), 2.06-1.99 (m, 2H).

Step 2: Mitsunobu Coupling Example 67 Preparation of methyl2-(5-{3-[(5-cyano-2-pyridinyl)oxy]propoxy}-1H-indol-1-yl)propanoate

To a solution of 6-(3-hydroxypropoxy)nicotinonitrile (Example 66, 0.55g, 3.09 mmol) and methyl 2-(5-hydroxy-1H-indol-1-yl)propanoate (Example7, 0.34 g, 1.55 mmol) in CH₂Cl₂ (7.73 mL) were added triphenylphosphine(0.61 g, 2.32 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.59 g, 2.32mmol). The yellow reaction mixture was stirred at rt for 18 h and thenconcentrated under reduced pressure. The crude residue was purified bysilica gel column chromatography (eluting with 67% hexanes/EtOAc) togive the title compound (0.5 g, 85%). ¹H NMR (400 MHz, CD₂Cl₂) δ 8.49(dd, 1H), 7.79 (dd, 1H), 7.25-7.09 (m, 3H), 6.85-6.83 (m, 2H), 6.47 (d,1H), 5.11 (qt, 1H), 4.60 (t, 2H), 4.17 (t, 2H), 3.71 (s, 3H), 2.35-2.25(m, 2H), 1.82 (d, 3H).

Step 3: Thioamide Formation Example 68 Preparation of methyl2-[5-(3-{[5-(aminocarbonothioyl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoate

H₂S gas was passed slowly through a solution of methyl2-(5-{3-[(5-cyano-2-pyridinyl)oxy]propoxy}-1H-indol-1-yl)propanoate(Example 67, 0.50 g, 1.32 mmol) in DMF (7.80 mL) for 20 minutes at rt.Diethylamine (0.21 mL, 2.37 mmol) was added in one portion, and theresultant light green solution was heated at 60° C. for 3 h. Thereaction mixture was purged with a stream of argon, and thenconcentrated under reduced pressure. The desired compound (0.49 g, 90%)was isolated by column chromatography (50% hexanes in EtOAc) as a brightyellow solid. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.63 (dd, 1H), 8.16 (dd, 1H),7.25-7.08 (m, 3H), 6.86-6.74 (m, 2H), 6.46 (d, 1H), 5.16 (qt, 1H), 4.59(t, 2H), 4.17 (t, 2H), 3.71 (s, 3H), 2.35-2.25 (m, 2H), 1.82 (d, 3H).

Step 4: Thiazole Formation Example 69 Preparation of methyl2-[5-(3-{[5-(4-ethyl-1,3-thiazol-2-yl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoate

A mixture of methyl2-[5-(3-{[5-(aminocarbonothioyl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoate(Example 68, 0.1 g, 0.24 mmol) and 1-bromo-2-butanone (0.05 g, 0.29mmol) in ethanol (8.90 mL) was heated under argon at 80° C. for 3 h. Theresulting mixture was concentrated. The title compound (0.11 g, 98%) wasisolated by column chromatography (2:1 hexanes/EtOAc). ¹H NMR (400 MHz,CD₂Cl₂) δ 8.69 (dd, 1H), 8.13 (dd, 1H), 7.25-7.10 (m, 3H), 6.90-6.81 (m,3H), 6.47 (d, 1H), 5.12 (qt, 1H), 4.58 (t, 2H), 4.20 (t, 2H), 3.71 (s,3H), 2.85 (qt, 2H), 2.36-2.24 (m, 2H), 1.82 (d, 3H), 1.35 (t, 3H).

Step 5: Hydrolysis Example 70 Preparation of2-[5-(3-{[5-(4-ethyl-1,3-thiazol-2-yl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoicacid

Lithium hydroxide (0.05 g, 2.15 mmol) was added to a solution of methyl2-[5-(3-{[5-(4-ethyl-1,3-thiazol-2-yl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoate(Example 69, 0.1 g, 0.21 mmol) in a mixture of THF (2 mL), methanol (2mL), and water (1 mL). The reaction mixture was stirred at rt for 18 hand then concentrated under reduced pressure. The residue was dilutedwith water and acidified with 5% H₃PO₄. The aqueous layer was extractedwith ethyl acetate. The combined organic extracts were dried overNa₂SO₄, filtered, and concentrated to give the title compound as a solid(0.079 g, 82%).

¹H NMR (400 MHz, CD₂Cl₂) δ 8.45 (dd, ₁H), 7.94 (dd, 1H), 7.08-6.62 (m,6H), 6.22 (d, 1H), 4.94 (qt, 1H), 4.37 (t, 2H), 4.00 (t, 2H), 2.66 (qt,2H), 2.31-2.07 (m, 2H), 1.60 (d, 3H), 1.15 (t, 3H).

Step 6: Chiral Separation Example 71 Separation of(2R)-2-[5-(3-{[5-(4-ethyl-1,3-thiazol-2-yl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoicacid and(2S)-2-[5-(3-{[5-(4-ethyl-1,3-thiazol-2-yl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoicacid

The racemic mixture of2-[5-(3-{[5-(4-ethyl-1,3-thiazol-2-yl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoicacid (Example 70, 0.3 g) was resolved by HPLC using a Pirkle covalent(R,R) whelk-02 chiral column, eluting with a gradient of 20 to 46% B (A:hexanes; B: 1:1 Methanol/Ethanol) over 13 minutes at a flow-rate of 25mL/min. This yielded 91 mg of the enantiomer, designated as Example 71A,with the retention time of 11.11 minutes. The other enantiomer,designated Example 71B, was eluted at retention time 9.62 minutes. ¹HNMR (400 MHz, CD₂Cl₂) δ 8.54 (dd, 1H), 8.01 (dd, 1H), 7.13-6.72 (m, 6H),6.25 (d, 1H), 4.96 (qt, 1H), 4.44 (t, 2H), 4.08 (t, 2H), 2.74 (qt, 2H),2.36-2.13 (m, 2H), 1.70 (d, 3H), 1.21 (t, 3H).

Step 1 and 2 Example 72 Preparation of6-(3-hydroxy-propoxy)-thionicotinamide

Through a solution of 6-(3-hydroxypropoxy)nicotinonitrile (Example 66,16 g, 89.79 mmol) in DMF (450 mL) was passed H₂S for 3 h at rt. Thereaction mixture turned purple. Diethylamine (9.85 g, 134.69 mmol) wasadded slowly. The resultant dark green solution was heated at 60° C. for2 h. The resulting mixture was concentrated under reduced pressure andpurified by flash chromatography with a gradient of EtOAc in hexanesfrom 50 to 100%. The title compound was collected as a yellow solid(18.9 g, 98%). ¹H NMR (400 MHz, acetone-d₆) δ 8.98-8.87 (br, 2H),8.80-8.79 (m, 1H), 8.29 (dd, 1H), 6.77 (dd, 1H), 4.48 (t, 2H), 3.74-3.68(m, 3H), 1.99 (t, 2H). LC/MS m/z 213.2 (M+H)⁺; RT 0.50 min.

Step 3: Thiazole Formation Example 73 Preparation of3-[5-(4-ethyl-thiazol-2-yl)-pyridin-2-yloxy]-propan-1-ol

To a solution of 6-(3-hydroxy-propoxy)-thionicotinamide (Example 72, 8.8g, 41.46 mmol) in EtOH (205 mL) at rt was added 1-bromo-2-butanone. Thereaction mixture was then heated at 70° C. for 3 h. Upon completion,triethylamine was added and the volatiles were removed under reducedpressure. The crude material was suspended in CH₂Cl₂ and purified byflash chromatography. The column was eluted with a mixture ofEtOAc/hexanes (30 to 50% EtOAc) to give the title compound as a whitesolid (10.04 g, 91%) after concentration of the chromatographyfractions. ¹H NMR (400 MHz, acetone-d₆) δ 8.70 (s, 1H), 8.19 (dd, 1H),7.15 (s, 1H), 6.86 (d, 1H), 4.48 (t, 2H), 3.74-3.71 (m, 3H), 2.83 (q,2H), 2.01-1.98 (m, 2H), 1.32 (t, 3H). LC/MS m/z 265.3 (M+H)⁺; RT 2.12min.

Step 4: Coupling Example 74 Preparation of(R)-2-(5-{3-[5-(4-ethyl-thiazol-2-yl)-pyridin-2-yloxy]-propoxy}-indol-1-yl)-propionicacid methyl ester

A solution of 3-[5-(4-ethyl-thiazol-2-yl)-pyridin-2-yloxy]-propan-1-ol(Example 73, 7.0 g, 0.025 mol), (R-2-(5-hydroxy-indol-1-yl)-propionicacid methyl ester (Example 8, 4.961 g, 0.023 mol), andtriphenylphosphine (7.716 g, 0.029 mol) in dichloromethane (60 mL) wastreated with a solution of 1,1′-(azodicarbonyl)-dipiperidine (7.423 g,0.029 mol) in dichloromethane (45 mL) slowly over 25 minutes whilemaintaining the temperature around 25° C. The resulting suspension wasstirred at rt for 18 h. Upon completion, the solvent was removed undervacuum and the crude product was purified by silica gel chromatographyusing a gradient of 5-35% ethyl acetate/hexanes to give 7.3 g (69%) ofthe title compound as a beige solid. The product was characterized as inExample 69.

Step 5: Hydrolysis Example 75 Preparation of(R)-2-(5-{3-[5-(4-ethyl-thiazol-2-yl)-pyridin-2-yloxy]-propoxy}-indol-1-yl)-propionicacid

A solution of(R)-2-(5-{3-[5-(4-ethyl-thiazol-2-yl)-pyridin-2-yloxy]-propoxy}-indol-1-yl)-propionicacid methyl ester (Example 74, 7.0 g, 0.015 mol) in THF (51 mL) andethanol (26 mL) was treated with a solution of lithium hydroxide (0.432g, 0.018 mol) in water (51 mL). The slightly hazy solution was stirredat rt for 2.5 h. The organic solvents were removed under vacuum at 30°C. The remaining suspension was diluted with water (50 mL). The pH ofthe mixture was adjusted to ˜5 using 1N HCl, and the mixture was stirredat rt for 1 h. The solid was filtered, washed with water (20 mL) anddried under high vacuum for 18-20 h.

To the resultant carboxylic acid (6.3 g) was added acetone (105 mL) and(R)-α-methylbenzylamine (1.93 mL, 0.015 mol). The reaction mixture washeated to ˜45° C. to achieve dissolution. The hot solution was gravityfiltered and allowed to cool to rt. It was then stirred at rt for 16-18h. The resulting precipitate was filtered, washed with acetone (13 mL),and dried under vacuum for 4-5 h. The dry salt was suspended in water(250 mL) and the pH of the suspension was adjusted to ˜5 with 1N HCl.The mixture was stirred for 1.5 h at rt, then filtered. The filter cakewas washed with water (50 mL) and dried under high vacuum at rt for18-20 h to give 3.6 g of the acid as a beige solid. The product wasrecrystallized from ethanol (52 mL) to give 2.7 g (40%) of the titlecompound (97% ee by chiral HPLC).

Chiral HPLC conditions: Column: Chiracel AD, 4.6 (I.D.)×250 mm; MobilePhase: A: 0.1% TFA in Hexanes; B: 0.1% TFA in IPA; Isocratic: 70% A (30%B) for 15 min; Flow rate: 1.0 mL/min; Detector (UV): 284 nm; retentiontime of the desired enantiomer: 11.53 min.

Step 1: Protection of Alcohol Example 76 Preparation of6-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-nicotinonitrile

To a solution of t-butyldimethylsilyl chloride (0.93 g, 6.17 mmol) inCH₂Cl₂ (25 mL) was added 6-(3-hydroxypropoxy)nicotinonitrile (Example66, 1 g, 5.61 mmol), Et₃N (0.62 g, 6.17 mmol), and DMAP (0.014 g, 0.11mmol). The mixture was stirred at rt for 18 h. The reaction mixture wasdiluted with brine and extracted with CH₂Cl₂ (3×25 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The crude residue was purified by silica gel flashchromatography (2:1 hexanes/EtOAc) to give the title compound (1.14 g,69%). ¹H NMR (400 MHz, CDCl₃) δ 8.40 (dd, 1H), 7.69 (dd, 1H), 6.72 (dd,1H), 4.40 (t, 2H), 3.73 (t, 2H), 1.90-1.98 (m, 2H), 0.82 (s, 9H), 0.02(s, 6H).

Step 2: Thiazole Formation Example 77 Preparation of2-{6-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-pyridin-3-yl}-4,5,6,7-tetrahydro-benzothiazole

H₂S gas was passed slowly through a solution of6-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-nicotinonitrile (Example76, 1.14 g, 3.90 mmol) in DMF (25.0 mL) at rt for 30 minutes.Diethylamine (0.60 mL, 5.85 mmol) was added in one portion, and theresultant light green solution was heated at 60° C. for 4 h. Thereaction mixture was purged with a stream of argon, and concentratedunder reduced pressure. The crude product was filtered through a shortpad of silica gel and eluted with EtOAc. The solvent was removed underreduced pressure. The residue was treated with a solution of2-chlorocyclohexanone (0.244 g, 1.80 mmol) in 10 mL 1:1 toluene/dioxane.The flask was connected to a Dean-Stark apparatus and heated at 150° C.for 18 h. The reaction mixture was concentrated under reduced pressure,the residue washed with water, and extracted with ethyl acetate. Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude material was purified bysilica gel flash chromatography (15% EtOAc in hexanes) to give the titlecompound (0.29 g, 18%). ¹H NMR (400 MHz, CDCl₃) δ 8.58 (dd, 1H), 8.02(dd, 1H), 6.65 (dd, 1H), 4.36 (t, 2H), 3.75 (t, 2H), 2.70-2.82 (m, 4H),1.90-1.98 (m, 2H), 1.80-1.90 (m, 4H), 0.82 (s, 9H), 0.02 (s, 6H).

Step 3: Deprotection to Alcohol Example 78 Preparation of3-[5-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-pyridin-2-yloxy]-propan-1-ol

A mixture of2-{6-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-pyridin-3-yl}-4,5,6,7-tetrahydro-benzothiazole(Example 77, 0.29 g, 0.71 mmol) in ethanol/HCl/water (95:1:4; 10 mL) wasstirred at rt for 18 h, and then concentrated under reduced pressure.The residue was purified by silica gel flash chromatography (1:4MeOH/CH₂Cl₂) to give the title compound (0.098 g, 46%). ¹H NMR (400 MHz,CDCl₃) δ 8.60 (dd, 1H), 8.10 (dd, 1H), 6.75 (dd, 1H), 4.51 (t, 2H), 3.73(t, 2H), 2.95-3.10 (broad s, 1H), 2.80-2.86 (m, 4H), 2.00-2.12 (m, 2H),1.80-1.96 (m, 4H).

Step 4 and 5: Coupling and Hydrolysis Example 79 Preparation of2-(5-{3-[5-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-pyridin-2-yloxy]-propoxy}-indol-1-yl)-propionicacid

To a solution of3-[5-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-pyridin-2-yloxy]-propan-1-ol(Example 78, 0.098 g, 0.34 mmol) and 2-(5-hydroxy-indol-1-yl)-propionicacid methyl ester (Example 7, 0.067 g, 0.31 mmol) in CH₂Cl₂ (10 mL) wereadded triphenylphosphine (0.161 g, 0.61 mmol) and1,1′-(azodicarbonyl)-dipiperidine (0.155 g, 0.61 mmol). The yellowreaction mixture was stirred at rt for 18 h, then diluted with 20 mLhexanes, and filtered through a short pad of silica gel. The filtratewas concentrated under reduced pressure, and the residue (0.065 g)dissolved in 5 mL of a mixture of methanol/THF/water (2:2:1). LiOH (9.1mg, 0.37 mmol) was added. The mixture was stirred at rt for 18 h andconcentrated under reduced pressure. The residue was taken up in waterand washed with ether. The aqueous layer was acidified to pH 3.5 andextracted with ethyl acetate. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated to give the title compound (7mg, 4%). ¹H NMR (400 MHz, acetone-d₆) δ 8.20 (dd, 1H), 7.90 (dd, 1H),7.35 (s, 1H), 7.29 (dd, 1H), 7.11 (s, 1H), 6.85 (dd, 1H), 6.50 (dd, 1H),6.39 (s, 1H), 5.25-5.35 (m, 1H), 4.31 (t, 2H), 4.31 (t, 2H), 4.08 (t,2H), 2.95-3.05 (br s, 1H), 2.70-2.78 (m, 4H), 2.30-2.35 (m, 2H),1.70-1.94 (m, 4H). LC/MS m/z 478.2 (M+H)⁺, RT 2.90 min.

Step 1: Aromatic Substitution Example 80 Preparation of3-(2-chloro-5-fluoro-pyrimidin-4-ylamino)-propan-1-ol

To a solution of 2,4-dichloro-5-fluoropyrimidine (15.0 g, 89.8 mmol) inethanol (300 mL) were added 3-amino-1-propanol (8.23 mL, 107.8 mmol) andsodium carbonate (47.6 g, 449 mmol). The reaction mixture was vigorouslystirred at rt for 72 h. Then the mixture was filtered through Celite®.The filtrate was concentrated under reduced pressure, and the residuewas purified by silica gel flash chromatography (100% EtOAc) to give thetitle compound as a white solid (9.5 g, 51%). LC/MS m/z 206.3 (M+H)⁺; ¹HNMR (300 MHz, CD₂Cl₂) δ 1.85 (quintet, 2H), 3.55 (t, 2H), 3.65 (t, 2H),4.85-4.98 (br, 2H), 7.85 (d, 1H).

Step 2: Protection of Alcohol Example 81 Preparation ofN-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-chloro-5-fluoro-4-pyrimidinamine

To a solution of t-butyldimethylsilyl chloride (1.63 g, 10.70 mmol) indichloromethane (48.63 mL) was added3-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-1-propanol (Example 80, 2.0g, 9.73 mmol), followed by triethylamine (1.49 mL, 10.70 mmol) anddimethylaminopyridine (0.02 g, 0.19 mmol). The resulting cloudy mixturewas stirred at rt for 18 h and then diluted with dichloromethane (80mL). The mixture was washed with water (50 mL), dried over magnesiumsulfate, and concentrated. The product was purified by columnchromatography (67% hexanes in EtOAc) to give the title compound as awhite solid (2.68 g, 86%). ¹H NMR (300 MHz, CD₂Cl₂) δ 7.78 (d, 1H),3.64-3.59 (m, 2H), 3.44-3.41(m, 2H), 1.82-1.73 (m, 2H), 0.84 (s, 9H),0.001 (s, 6H).

Step 3: N-Alkylation Example 82 Preparation ofN-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-chloro-5-fluoro-N-methyl-4-pyrimidinamine

Sodium hydride (0.4 g, 16.76 mmol) was added to a solution ofN-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-chloro-5-fluoro-4-pyrimidinamine(Example 81, 2.68 g, 8.38 mmol) in DMF (41.90 mL). The resulting mixturewas stirred at rt for 30 minutes. Methyl iodide (2.09 mL, 33.51 mmol)was added. The mixture was stirred at rt for additional 18 h, thenquenched with water, and extracted with ether. The combined etherextracts were washed with water (25 mL), brine (40 mL), dried overmagnesium sulfate, filtered, and concentrated. The title compound (2.76g, 99%) was obtained after column chromatography (67% hexanes in EtOAc).¹H NMR (300 MHz, CD₂Cl₂) δ 7.78 (d, 1H), 3.64-3.59 (m, 4H), 3.24 (d,3H), 1.82-1.73 (m, 2H), 0.84 (s, 9H), 0.001 (s, 6H).

Step 4: Deprotection to Alcohol Example 83 Preparation of3-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]-1-propanol

A mixture ofN-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-chloro-5-fluoro-N-methyl-4-pyrimidinamine(Example 82, 2.22 g, 6.65 mmol) in ethanol/HCl/water (95:1:4, 50 mL) wasstirred at rt for 18 h and then concentrated under reduced pressure. Theresidue was passed through a plug of silica gel to give the titlecompound (1.13 g, 77%) as a viscous yellow oil. ¹H NMR (300 MHz,DMSO-d₆) δ 8.08 (d, 1H), 3.59 (t, 2H), 3.43 (t, 2H), 3.24 (d, 3H),1.74-1.71 (m, 2H).

Step 5: Mitsunobu Coupling Example 84 Preparation of methyl(5-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]propoxy}-1H-indol-1-yl)acetate

To a solution of3-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]-1-propanol (Example83, 0.60 g, 2.73 mmol) and methyl (5-hydroxy-1H-indol-1-yl)acetate(Example 9, 0.37 g, 1.82 mmol) in dichloromethane (9 mL) was addedtriphenylphosphine (0.70 g, 2.73 mmol) and1,1′-(azodicarbonyl)-dipiperidine (0.72 g, 2.73 mmol) under argon. Thegolden yellow mixture was stirred at rt for 18 h. The desired product(0.42 g, 56%) was obtained after column chromatography (67% hexanes inEtOAc). ¹H NMR (300 MHz, CD₂Cl₂) δ 7.85 (d, 1H), 7.15-7.07 (m, 3H),6.88-6.83 (m, 1H), 6.47-6.46 (m, 1H), 4.85 (s, 2H), 4.07 (t, 2H), 3.84(t, 2H), 3.76 (s, 3H), 3.26 (d, 3H), 2.20-2.13 (m, 2H).

Example 85 Preparation of2-{5-[3-(2-chloro-5-fluoro-pyrimidin-4-ylamino)-propoxy]-indol-1-yl}-propionicacid methyl ester

To a solution of 3-(2-chloro-5-fluoro-pyrimidin-4-ylamino)-propan-1-ol(Example 80, 0.66 g, 3.20 mmol) and 2-(5-hydroxy-indol-1-yl)-propionicacid methyl ester (Example 7, 0.47 g, 2.13 mmol) in dichloromethane(10.80 mL) was added triphenylphosphine (0.85 g, 3.20 mmol) and1,1′-(azodicarbonyl)-dipiperidine (0.82 g, 3.20 mmol) under argon. Thegolden yellow mixture was stirred at rt for 18 h. The desired product(0.54 g, 59%) was obtained after column chromatography (67% hexanes inEtOAc). ¹H NMR (300 MHz, CD₃OD) δ 7.85 (d, 1H), 7.27-7.06 (m, 3H),6.82-6.79 (m, 1H), 6.40 (d, 1H), 5.24 (q, 1H), 4.11-4.07 (m, 2H),3.70-3.67 (m, 5H), 2.15-2.09 (m, 2H), 1.77 (d, 3H).

Step 6: Suzuki Coupling Example 86 Preparation of methyl(5-{3-[[5-fluoro-2-(4-methoxyphenyl)-4-pyrimidinyl](methyl)amino]propoxy}-1H-indol-1-ylacetate

To a solution of methyl(5-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]propoxy}-1H-indol-1-yl)acetate(Example 84, 0.1 g, 0.25 mmol) in toluene (3.75 mL), dioxane (0.75 mL),and water (0.88 mL) were added sodium carbonate (0.26 g, 2.46 mmol),4-methoxyphenyl boronic acid (0.15 g, 0.98 mmol), andPdCl₂(dppf)(CH₂Cl₂) (0.04 g, 0.05 mmol). The mixture was heated at 80°C. for 4 h and then concentrated under reduced pressure. The product(0.11 g, 94%) was obtained after column chromatography (67% hexanes inEtOAc). ¹H NMR (300 MHz, CD₂Cl₂) δ 8.31 (d, 2H), 8.06 (d, 1H), 7.12-7.07(m, 3H), 6.95-6.87 (m, 3H), 6.41 (d, 1H), 4.85 (s, 2H), 4.11 (t, 2H),3.94 (t, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.35 (d, 3H), 2.26-2.20 (m,2H).

Step 7: Hydrolysis Example 87 Preparation of(5-{3-[[5-fluoro-2-(4-methoxyphenyl)-4-pyrimidinyl](methyl)amino]propoxy}-1H-indol-1-yl)aceticacid

To a solution of methyl(5-{3-[[5-fluoro-2-(4-methoxyphenyl)-4-pyrimidinyl](methyl)amino]propoxy}-1H-indol-1-yl)acetate(Example 86, 0.1 g, 0.20 mmol) in methanol (2 mL), THF (2.00 mL), andwater (1.00 mL) was added lithium hydroxide (0.05 g, 1.99 mmol). Themixture was stirred at rt for 18 h and then concentrated under reducedpressure. The residue was taken up in water and washed with ether. Theaqueous layer was acidified to pH 3.5 and extracted with ethyl acetate.The combined organic layers were dried over sodium sulfate andconcentrated to give the title compound (0.092 g, 100%). ¹H NMR (300MHz, CD₃OD) δ 8.20-8.17 (m, 2H), 8.03-8.01 (m, 1H), 7.18-6.78 (m, 6H),6.33-6.30 (m, 1H), 4.74 (s, 2H), 4.11 (t, 2H), 3.94 (t, 2H), 3.83 (s,3H), 3.36-3.34 (m, 3H), 2.26-2.20 (m, 2H). LC/MS m/z 465.2 (M+H)⁺, RT2.51 min.

Step 1: Mitsunobu Coupling Example 88 Preparation of(2-chloro-5-methyl-pyrimidin-4-yl)-[3-(1H-indol-5-yloxy)-propyl]-methyl-amine

To a solution of3-[(2-chloro-5-methyl-4-pyrimidinyl)(methyl)amino]-1-propanol (0.316 g,1.47 mmol) (prepared in similar fashion as Example 83) and5-hydroxyindole (0.195 g, 1.47 mmol) in dichloromethane (7 mL) was addedtriphenylphosphine (1.15 g, 4.40 mmol) and1,1′-(azodicarbonyl)dipiperidine (1.11 g, 4.40 mmol) under argon. Thegolden yellow mixture was stirred at rt for 24 h. The desired product(0.117 g, 24%) was obtained after column chromatography (50% hexanes inEtOAc). LC/MS m/z 331.3 (M+H)⁺, RT 2.76 min.

Step 2 Example 89 Preparation of(5-{3-[(2-chloro-5-methyl-pyrimidin-4-yl)-methyl-amino]-propoxy}-indol-1-yl)-aceticacid ethyl ester

(2-Chloro-5-methyl-pyrimidin-4-yl)-[3-(1H-indol-5-yloxy)-propyl]-methyl-amine(Example 88, 0.117 g, 0.35 mmol) was dissolved in DMF (2 mL) at rt, andsodium hydride was added (0.017 g, 60% in mineral oil, 0.42 mmol). Thereaction solution immediately turned purple. The resulting mixture wasstirred for 1 h and ethyl bromoacetate (0.065 g, 0.39 mmol) was added.The reaction mixture was stirred for 60 h, diluted with water, andextracted with EtOAc. The organic phases were dried over sodium sulfate,filtered, and concentrated under reduced pressure to give the titlecompound as an orange oil without purification (103 mg, 70%). LC/MS m/z417.4 (M+H)⁺, RT 3.05 min.

Step 3: Suzuki Coupling Example 90 Preparation of[5-(3-{[2-(4-fluoro-phenyl)-5-methyl-pyrimidin-4-yl]-methyl-amino}-propoxy)-indol-1-yl]-aceticacid ethyl ester

Using the compound from Example 89 as starting material, the titlecompound was prepared as described in Example 86 to give the titlecompound (316 mg, 83%). LC/MS m/z 477.3 (M+H)⁺, RT 3.53 min.

Step 4: Hydrolysis Example 91 Preparation of[5-(3-{[2-(4-fluoro-phenyl)-5-methyl-pyrimidin-4-yl]-methyl-amino}-propoxy)-indol-1-yl]-aceticacid

Using the compound from Example 90 as starting material, the titlecompound was prepared in similar fashion as described in Example 87(heated at 50° C. for 3 h) to give the title compound as a white solid(316 mg, 83). LC/MS m/z 449.3 (M+H)⁺, RT 2.26 min.

Method 17: Preparation of Pyrimidine Aminoalkoxy Indoles

Alkylations on the nitrogen and carbon were performed as shown inExample 92; Suzuki coupling and basic hydrolysis were performed insimilar fashion shown in the examples under Method 16.

Step 1: C- and N-Alkylation Example 92 Preparation of2-(5-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]-propoxy}-indol-1-yl)propanoicacid

Sodium hydride (0.04 g, 1.78 mmol) was added to a solution of methyl(5-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]propoxy}-1H-indol-1-yl)acetate(0.35 g, 0.89 mmol, prepared in similar fashion as Example 86) in DMF(4.5 mL). After stirring the reaction mixture at rt for 30 minutes,methyl iodide (0.22 mL, 3.56 mmol) was added. The mixture was stirred atrt for additional 18 h, quenched with water, and extracted with ether.The combined ether extracts were washed with water and brine. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated under vacuum. The desired product (0.11 g, 28%) wasobtained after column chromatography (67% hexanes in EtOAc). ¹H NMR (300MHz, CD₂CO₂) δ 7.84 (d, 1H), 7.25-7.06 (m, 3H), 6.85-6.82 (m, 0H),6.47-6.46 (m, 1H), 5.12 (q, 1H), 4.06 (t, 2H) 3.84 (t, 2H), 3.71 (s,3H), 3.25 (d, 3H), 2.19-2.12 (m, 2H), 1.12 (d, 3H). LC/MS m/z 421.1(M+H)⁺, RT 3.35 min.

By substituting the appropriate starting materials, and by using theabove described methods other compounds of the invention may besimilarly prepared. Example compounds of the invention are summarizedbelow in Table 1. Meth- ods of Entry M + H RT Prepa- No. Structure IUPACName (ES) (min) ration  1

(5-{3-[3-(1,1-difluoro- ethyl)-7-propyl-benzo[d]isoxazol-6-yloxy]-propoxy}-indol-1-yl)- acetic acid 424.3 4.09 1, 7, 11  2

2-{5-[3-(7-propyl-3-tri- fluoromethyl-benzo[d]isoxazol-6-yloxy)-propoxy]-indol-1-yl}- propionic acid 491.2 4.02 1, 7, 11  3

{5-[2-(1,6-dibromo- naphthalen-2-yloxy)- ethoxy]-indol-1-yl}- aceticacid 520   3.76 1, 3  4

2-{5-[2-(1,6-dibromo- naphthalen-2-yloxy)- ethoxy]-indol-1-yl}-propionic acid 534   3.82 1, 3  5

(2S)-2-{5-[2-(1,6- dibromo-naphthalen-2- yloxy)-ethoxy]-indol-1-yl}-propionic acid 534   3.85 1, 3  6

(2R)-2-{5-[2-(1,6- dibromo-naphthalen-2- yloxy)-ethoxy]-indol-1-yl}-propionic acid 534   3.85 1, 3  7

2-{5-[2-(4-ethyl-2- methoxy-phenoxy)- ethoxy]-indol-1-yl}- propionicacid 384   3.27 1, 3  8

2-{5-[2-(2-methoxy-4- methyl-phenoxy)- ethoxy]-indol-1-yl}- propionicacid 370   3.11 1, 3  9

2-{5-[2-(2-chloro-4- methyl-phenoxy)- ethoxy]-indol-1-yl}- propionicacid 74  3.37 1, 3 10

2-{5-[3-(2-methoxy-4- methyl-phenoxy)- propoxy]-indol-1-yl}- propionicacid 384   3.22 1, 3 11

2-{5-[2-(4-bromo-2- chloro-phenoxy)- ethoxy]-indol-1-yl}- propionic acid439   3.54 1, 3 12

2-{5-[2-(2-cyano-4- methoxy-phenoxy)- ethoxy]-indol-1-yl}- propionicacid 381   2.93 1, 3 13

{5-[3-(4-cyano-2- methoxy-phenoxy)- propoxy]-3-methyl-indol-1-yl}-acetic acid 395   3.45 1, 4, 8 14

{6-[3-(7-propyl-3- trifluoromethyl-benzo[d]isoxazol-6-yloxy)-propoxy]-1H-indol-3- yl}-acetic acid 476.9 3.84 2, 7, 11 15

(5-{3-[4-(4-ethyl-oxazol- 2-yl)-phenoxy]- propoxy}-indol-1-yl)- aceticacid 421.1 3.22 1, 5, 10 16

(5-{3-[4-(4,5,6,7- tetrahydro-benzooxazol- 2-yl)-phenoxy]-propoxy}-indol-1-yl)- acetic acid 447.3 3.37 1, 5, 10 17

(5-{3-[4-(5-acetyl-4- methyl-oxazol-2-yl)- phenoxy]-propoxy}-indol-1-yl)-acetic acid 449.1 3.17 1, 5, 10 18

(5-{3-[4-(5-acetyl-4- methyl-oxazol-2-yl)-2- propyl-phenoxy]-propoxy}-indol-1-yl)- acetic acid 491.1 3.61 1, 5, 10 19

(5-{3-[4-(5-acetyl-4- methyl-oxazol-2-yl)-2- propyl-phenoxy]-propoxy}-3-methyl- indolyl)-acetic acid 505.3 3.69 1, 5, 10 20

(5-{3-[4-(5-acetyl-4- methyl-oxazol-2-yl)-2- methoxy-phenoxy]-propoxy}-indol-1-yl)- acetic acid 479.3 2.99 1, 5, 10 21

(5-{3-[4-(4-trifluoro- methyl-oxazol-2-yl)- phenoxy]-propoxy}-indol-1-yl)-acetic acid 461.1 3.52 1, 5, 10 22

(5-{3-[4-(4-tert-butyl- oxazol-2-yl)-phenoxy]- propoxy}-indol-1-yl)-acetic acid 3.65 1, 5, 10 23

(5-{3-[3-(4-ethyl-oxazol- 2-yl)-phenoxy]- propoxy}-indol-1-yl)- aceticacid 421.2 3.33 1, 6, 10 24

(5-{3-[3-(4,5,6,7-tetra- hydro-benzooxazol-2-yl)- phenoxy]-propoxy}-indol-1-yl)-acetic acid 447.2 3.47 1, 6, 10 25

(5-{3-[3-(5-hydroxy-4- trifluoromethyl-4,5- dihydro-oxazol-2-yl)-phenoxy]-propoxy}- indol-1-yl)-acetic acid 479.1 3.04 1, 6, 10 26

(5-{3-[2-methoxy-4- (4,5,6,7-tetrahydro- benzooxazol-2-yl)-phenoxy]-propoxy}- indol-1-yl)-acetic acid 477.2 3.34 1, 5, 10 27

(5-{3-[2-methoxy-4- (4-trifluoromethyl- oxazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)- acetic acid 491.1 3.37 1, 5, 10 28

(5-{3-[4-(4-tert-butyl- oxazol-2-yl)-2-methoxy- phenoxy]-propoxy}-indol-1-yl)-acetic acid 479.3 3.53 1, 5, 10 29

(5-{3-[4-(4-ethyl- oxazol-2-yl)-2-methoxy- phenoxy]-propoxy}-indol-1-yl)-acetic acid 451.2 3.15 1, 5, 10 30

(5-{3-[4-(4-ethyl- oxazol-2-yl)-2-propyl- phenoxy]-propoxy}-indol-1-yl)-acetic acid 463.2 3.77 1, 6, 10 31

(5-{3-[2-propyl-4- (4,5,6,7-tetrahydro- benzooxazol-2-yl)-phenoxy]-propoxy}- indol-1-yl)-acetic acid 489.2 3.92 1, 6, 10 32

(5-{3-[4-(4-tert-butyl- oxazol-2-yl)-2-propyl- phenoxy]-propoxy}-indol-1-yl)-acetic acid 491.2 4.19 1, 6, 10 33

(5-{3-[4-(4-tert-butyl- oxazol-2-yl)-2-propyl- phenoxy]-propoxy}-3-methylindolyl)-acetic acid 505.5 4.27 1, 5, 10 34

2-(5-{3-[4-(4-tert-butyl- oxazol-2-yl)-phenoxy]- propoxy}-indol-1-yl)-propionic acid 463.2 3.87 1, 5, 10 35

2-(5-{3-[4-(4-trifluoro- methyl-oxazol-2-yl)- phenoxy]-propoxy}-indol-1-yl)-propionic acid 465.1 3.64 1, 5, 10 36

2-(5-{3-[4-(4,5,6,7- tetrahydro-benzooxazol- 2-yl)-phenoxy]-propoxy}-indol-1-yl)- propionic acid 461.3 3.52 1, 5, 10 37

2-(5-{3-[4-(5-acetyl-4- methyl-oxazol-2-yl)- phenoxy]-propoxy}-indol-1-yl)-propionic acid 463.2 3.23 1, 5, 10 38

2-(5-{3-[2-methoxy-4- (4,5,6,7-tetrahydro- benzooxazol-2-yl)-phenoxy]-propoxy}- indol-1-yl)-propionic acid 491.4 3.39 1, 5, 10 39

2-(5-{3-[4-(5-acetyl-4- methyl(1,3-oxazol-2-yl))-2-methoxyphenoxy]propoxy}indolyl) propanoic acid 493.3 3.13 1, 5, 10 40

2-(5-{3-[4-(4-ethyl(1,3- oxazol-2-yl))-2-methoxy-phenoxy]propoxy}indolyl)propanoic acid 465.1 3.25 1, 5, 10 41

2-(5-{3-[4-(4-ethyl(1,3- oxazol-2-yl))-phenoxy]propoxy}indolyl)propanoic acid 435.1 3.46 1, 5, 10 42

2-{5-[3-(2-propyl-4- (4,5,6,7-tetrahydro- benzoxazol-2-yl)phenoxy)propoxy]indolyl}propanoic acid 503.5 3.99 1, 5, 10 43

2-(5-{3-[4-(4-ethyl(1,3- oxazol-2-yl))-2-methoxy- phenoxy]propoxy}-3-methylindolyl)acetic acid 465.1 3.27 1, 5, 10 44

2-[5-(3-{2-methoxy-4- [4-(trifluoromethyl)(1,3-oxazol-2-yl)]phenoxy}propoxy)-3-methyl- indolyl]acetic acid 505   3.511, 5, 10 45

2-(5-{3-[4-(5-acetyl-4- methyl(1,3-oxazol-2-yl))-2-methoxyphenoxy]propoxy}-3-methyl- indolyl)acetic acid 493.2 3.14 1, 5,10 46

2-(5-{3-[4-(4-ethyl(1,3- oxazol-2-yl))-2-propyl- phenoxy]propoxy}-3-methylindolyl)acetic acid 477.4 3.88 1, 5, 10 47

2-[5-(3-{4-[4-(tert-butyl) (1,3-oxazol-2-yl)]phenoxy}propoxy)-3-methylindolyl]propanoic acid 477.2 4   1, 5, 10 48

2-[3-methyl-5-(3-{4-[4- (trifluoromethyl)(1,3-oxazol-2-yl)]phenoxy}propoxy)indolyl]propanoic acid 489.1 3.76 1, 5, 1049

2-{3-methyl-5-[3-(4- (4,5,6,7-tetrahydro- benzoxazol-2-yl)phenoxy)propoxy]indolyl}propanoic acid 475.3 3.7  1, 5, 10 50

2-(5-{3-[4-(4-ethyl(1,3- oxazol-2-yl))phenoxy]propoxy}-3-methyl-indolyl)propanoic acid 449.3 3.57 1, 5, 10 51

2-{5-[3-(2-methoxy-4- (4,5,6,7-tetrahydro- benzoxazol-2-yl)phenoxy)propoxy]-3- methylindolyl}propanoic acid 505.4 3.53 1, 5, 10 52

2-(5-{3-[4-(4-ethyl(1,3- oxazol-2-yl))-2-methoxy- phenoxy]propoxy}-3-methylindolyl)propanoic acid 479.1 3.41 1, 5, 10 53

2-{3-methyl-5-[3-(2- propyl-4-(4,5,6,7-tetra- hydrobenzoxazol-2-yl)phenoxy)propoxy]indolyl}propanoic acid 517.5 4.11 1, 5, 10 54

2-{5-[3-(4-(4,5,6,7- tetrahydrobenzothiazol-2-yl)phenoxy)propoxy]indolyl}acetic acid 463.1 3.5  1, 4, 9 55

2-(5-{3-[4-(4,5-dimethyl-1,3-thiazol-2-yl)phenoxy]propoxy}indolyl)acetic acid 437.1 3.21 1, 4, 956

(5-{3-[3-(4,5,6,7- tetrahydro-benzothiazol- 2-yl)-phenoxy]-propoxy}-indol-1-yl)- acetic acid 463.2 3.6  1, 4, 9 57

2-[5-(3-{2-methoxy-4- [4-(methylethoxy)(1,3-thiazol-2-yl)]phenoxy}propoxy)indolyl]acetic acid 497.1 3.42 1, 4, 9 58

2-(5-{3-[4-(4,5-dimethyl (1,3-thiazol-2-yl))-2-methoxyphenoxy]propoxy}indolyl)acetic acid 467.3 3.04 1, 4, 9 59

2-{5-[3-(2-methoxy-4- (4,5,6,7-tetrahydro- benzothiazol-2-yl)phenoxy)propoxy]indolyl}acetic acid 493.2 3.37 1, 4, 9 60

2-(5-{3-[4-(4-ethoxy-5- methyl(1,3-thiazol-2-yl))-2-methoxyphenoxy]propoxy}indolyl)acetic acid 497.1 3.72 1, 4, 9 61

2-{5-[3-(2-methoxy-4- (1,3-thiazol-2-yl) phenoxy)propoxy]indolyl}aceticacid 439.1 3.01 1, 4, 9 62

(5-{3-[4-(4-ethyl- thiazol-2-yl)-2-propyl- phenoxy]-propoxy}-indol-1-yl)-acetic acid 479.1 3.83 1, 4, 8 63

(5-{3-[4-(4-ethyl- thiazol-2-yl)-2-methoxy- phenoxy]-propoxy}-indol-1-yl)-acetic acid 467.1 3.3  1, 4, 8 64

2-{5-[3-(2-propyl-4- (4,5,6,7-tetrahydro- benzothiazol-2-yl)phenoxy)propoxy]indolyl}acetic acid 505.4 3.88 1, 4, 9 65

2-(5-{3-[4-(4-ethoxy- 5-methyl(1,3-thiazol-2-yl))-2-propylphenoxy]propoxy}indolyl)acetic acid 509.4 4.31 1, 4, 9 66

2-(5-{3-[4-(4-ethoxy- 5-methyl(1,3-thiazol-2-yl))-2-propylphenoxy]propoxy}-3-methyl- indolyl)acetic acid 523.2 4.421, 4, 9 67

2-[5-(3-{4-[5-(N,N- dimethylcarbamoyl)-4- methyl(1,3-thiazol-2-yl)]-2-propylphenoxy}propoxy)indolyl]acetic acid 536.1 3.36 1, 4, 8 68

2-{5-[3-(2-propyl-4-(1,3- thiazol-2-yl)phenoxy) propoxy]indolyl}aceticacid 451.3 3.57 1, 4, 9 69

(5-{3-[4-(6,7-dihydro- 5H-pyrano[2,3-d]thiazol- 2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)- acetic acid 507.4 3.8  1, 4, 9 70

2-(5-{3-[4-(4,5,6,7- tetrahydro-benzothiazol- 2-yl)-phenoxy]-propoxy}-indol-1-yl)- propionic acid 477.2 3.52 1, 4, 9 71

2-(5-{3-[4-(4,5,6,7- tetrahydro-benzothiazol- 2-yl)-phenoxy]-propoxy}-indol-1-yl)- propionic acid 477.2 3.52 1, 4, 9 72

2-[5-(3-{2-methoxy-4- [4-(methylethoxy)(1,3-thiazol-2-yl)]phenoxy}propoxy)indolyl]propanoic acid 511.3 3.56 1, 4, 973

2-(5-{3-[4-(4-ethyl(1,3- thiazol-2-yl))-2-methoxy-phenoxy]propoxy}indolyl)propanoic acid 481.3 3.36 1, 4, 9 74

2-{5-[3-(2-methoxy-4- (4,5,6,7-tetrahydro- benzothiazol-2-yl)phenoxy)propoxy]indolyl}propanoic acid 507.1 3.48 1, 4, 9 75

2-(5-{3-[4-(4-ethoxy-5- methyl(1,3-thiazol-2-yl))-2-methoxyphenoxy]propoxy}indolyl) propanoic acid 511.1 3.83 1, 4, 9 76

2-(5-{3-[4-(4-ethoxy-5- methyl(1,3-thiazol-2-yl))-2-propylphenoxy]propoxy}indolyl) propanoic acid 523.1 4.46 1, 4, 9 77

(2S)-2-(5-{3-[4-(4- ethoxy-5-methyl-thiazol- 2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)- propionic acid 523.3 4.47 1, 4, 9 78

(2R)-2-(5-{3-[4-(4- ethoxy-5-methyl-thiazol- 2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)- propionic acid 523.3 4.47 1, 4, 9 79

2-{5-[3-(2-propyl-4- (4,5,6,7-tetrahydro- benzothiazol-2-yl)phenoxy)propoxy]indolyl}propanoic acid 519.2 3.99 1, 4, 9 80

2-(5-{3-[4-(4,5- dimethyl(1,3-thiazol-2- yl))phenoxy]propoxy}-3-methylindolyl)acetic acid 451   3.34 1, 4, 9 81

(3-methyl-5-{3-[4- (4,5,6,7-tetrahydro- benzothiazol-2-yl)-phenoxy]-propoxy}- indol-1-yl)-acetic acid 477   3.63 1, 4, 9 82

2-[5-(3-{2-methoxy-4- [4-(methylethoxy)(1,3-thiazol-2-yl)]phenoxy}propoxy)-3-methyl- indolyl]acetic acid 511   3.571, 4, 9 83

2-(5-{3-[4-(4,5- dimethyl(1,3-thiazol-2-yl))-3-methoxyphenoxy]propoxy}-3-methyl- indolyl)acetic acid 481.1 3.211, 4, 9 84

2-{5-[3-(2-methoxy-4- (4,5,6,7-tetrahydro- benzothiazol-2-yl)phenoxy)propoxy]-3- methylindolyl}acetic acid 507.1 3.47 1, 4, 9 85

2-{3-methyl-5-[3-(2- propyl-4-(4,5,6,7- tetrahydrobenzothiazol-2-yl)phenoxy)propoxy]indolyl}acetic acid 519.2 3.99 1, 4, 9 86

2-{3-methyl-5-[3-(4- (4,5,6,7-tetrahydro- benzothiazol-2-yl)phenoxy)propoxy]indolyl}propanoic acid 491   3.76 1, 4, 9 87

2-(5-{3-[4-(4,5- dimethyl(1,3-thiazol-2- yl))phenoxy]propoxy}-indol-1-yl)propanoic acid 481.2 3.71 1, 4, 9 88

2-(5-{3-[4-(4,5-dimethyl (1,3-thiazol-2-yl)) phenoxy]propoxy}-3-methylindolyl) propanoic acid 465   3.46 1, 4, 9 89

2-(5-{3-[4-(4,5-dimethyl (1,3-thiazol-2-yl))-2-methoxyphenoxy]propoxy}-3-methyl- indolyl)propanoic acid 495.1 3.33 1,4, 9 90

2-{5-[3-(2-methoxy-4- (4,5,6,7-tetrahydro- benzothiazol-2-yl)phenoxy)propoxy]-3- methylindolyl}propanoic acid 521.2 3.59 1, 4, 9 91

2-(5-{3-[4-(4-ethyl (1,3-thiazol-2-yl))-2-methoxyphenoxy]propoxy}-3-methyl- indolyl)propanoic acid 495.1 3.53 1,4, 9 92

2-[5-(3-{2-methoxy-4-[4- (methylethoxy)(1,3-thiazol-2-yl)]phenoxy}propoxy)-3-methyl- indolyl]propanoic acid 525.13.73 1, 4, 9 93

2-(5-{3-[4-(4-ethoxy-5- methyl(1,3-thiazol-2-yl))-2-methoxyphenoxy]propoxy}-3-methyl- indolyl)propanoic acid 525.1 3.98 1,4, 9 94

2-(5-{3-[4-(4-ethoxy-5- methyl(1,3-thiazol-2-yl))-2-propylphenoxy]propoxy}-3-methyl- indolyl)propanoic acid 537.4 4.6  1,4, 9 95

(2S)-2-(5-{3-[4-(4- ethoxy-5-methyl-thiazol- 2-yl)-2-propyl-phenoxy]-propoxy}-3-methyl- indol-1-yl)propionic acid 537.3 4.6  1, 4, 9 96

(2R)-2-(5-{3-[4-(4- ethoxy-5-methyl-thiazol- 2-yl)-2-propyl-phenoxy]-propoxy}-3-methyl- indol-1-yl)propionic acid 537.3 4.6  1, 4, 9 97

2-{3-methyl-5-[3-(2- propyl-4-(4,5,6,7- tetrahydrobenzothiazol-2-yl)phenoxy)propoxy]indolyl}propanoic acid 533.2 4.13 1, 4, 9 98

(2S)-2-(3-methyl-5-{3- [2-propyl-4-(4,5,6,7- tetrahydro-benzothiazol-2-yl)-phenoxy]- propoxy}-indol-1-yl)- propionic acid 533.3 4.13 1, 4, 999

(2R)-2-(3-methyl-5-{3- [2-propyl-4-(4,5,6,7- tetrahydro-benzothiazol-2-yl)-phenoxy]- propoxy}-indol-1-yl)- propionic acid 533.3 4.13 1, 4, 9100 

(3-ethyl-5-{3-[2-propyl- 4-(4,5,6,7-tetrahydro- benzothiazol-2-yl)-phenoxy]-propoxy}- indol-1-yl)-acetic acid 533   4.43 1, 4, 9 101 

(5-{3-[5-(5-acetyl-4- methyl-thiazol-2-yl)- pyridin-2-yloxy]-propoxy}-indol-1-yl)- acetic acid 466   3.1  1, 12 102 

2-(5-{3-[5-(4-ethoxy- 1,3-thiazol-2-yl)-2-pyridyloxy]propoxy}indolyl)acetic acid 454   3.23 1, 12 103 

2-(5-{3-[5-(4,5-dimethyl- 1,3-thiazol-2-yl)-2-pyridyloxy]propoxy}indolyl)acetic acid 438.1 3.14 1, 12 104 

2-(5-{3-[5-(4-ethyl- 1,3-thiazol-2-yl)-2-pyridyloxy]propoxy}indolyl)acetic acid 438.1 3.26 1, 12 105 

(5-{3-[5-(4-ethyl-thiazol- 2-yl)-pyridin-2-yloxy]- propoxy}-3-methyl-indol-1-yl)-acetic acid 452   3.47 1, 14 106 

2-(5-{3-[5-(4-ethyl-1,3- thiazol-2-yl)-2-pyridyloxy]propoxy}indolyl)propanoic acid 452.1 3.41 1, 12 107 

(2S)-2-(5-{3-[5-(4-ethyl (1,3-thiazol-2-yl))(2-pyridyloxy)]propoxy}indolyl)propanoic acid 452.1 3.38 1, 12 108 

(2R)-2-(5-{3-[5-(4-ethyl (1,3-thiazol-2-yl))(2-pyridyloxy)]propoxy}indolyl)propanoic acid 452.1 3.42 1, 12, 13 109 

2-(5-{3-[5-(5-acetyl-4- methyl-1,3-thiazol-2-yl)-2-pyridyloxy]propoxy}indolyl)propanoic acid 480   3.32 1, 12 110 

2-(5-{3-[5-(4-ethoxy-5- methyl-1,3-thiazol-2-yl)-2-pyridyloxy]propoxy}indolyl)propanoic acid 482   3.88 1, 12 111 

(2S)-2-(5-{3-[5-(4- ethoxy-5-methyl-thiazol- 2-yl)-pyridin-2-yloxy]-propoxy}-indol-1-yl)- propionic acid 482   3.88 1, 12 112 

(2R)-2-(5-{3-[5-(4- ethoxy-5-methyl-thiazol- 2-yl)-pyridin-2-yloxy]-propoxy}-indol-1-yl)- propionic acid 482   3.88 1, 12 113 

2-(5-{3-[5-(4,5,6,7- tetrahydro-benzothiazol- 2-yl)-pyridin-2-yloxy]-propoxy}-indol-1-yl)- propionic acid 478.2 2.9  1, 14 114 

2-[5-(3-{[2-(4- ethylphenyl)-5-methyl- pyrimidin-4-yl]methyl-amino}propoxy) indolyl]acetic acid 459.3 2.48 1, 15 115 

2-(5-{3-[(2-(2H-benzo [3,4-d]1,3-dioxolan-5- yl)-5-methylpyrimidin-4-yl)methylamino]propoxy}indolyl)acetic acid 475.3 2.79 1, 15 116 

2-[5-(3-{[2-(4- fluorophenyl)-5-methyl- pyrimidin-4-yl]methyl-amino}propoxy)indolyl]acetic acid 449.3 2.26 1, 16 117 

2-(5-{3-[(2-benzo[1,3]dioxol-5-yl-pyrimidin-4- yl)-methyl-amino]-propoxy}-indol-1-yl)- propionic acid 475.3 2.26 1, 15 118 

2-[5-(3-{[2-(4-ethyl- phenyl)-5-fluoro- pyrimidin-4-yl]methyl-amino}propoxy)indolyl]acetic acid 463.2 2.28 1, 15 119 

2-[5-(3-{[5-fluoro-2- (4-methoxyphenyl) pyrimidin-4-yl]methyl-amino}propoxy)indolyl]acetic acid 465.2 2.51 1, 15 120 

2-(5-{3-[(2-(2H-benzo [3,4-d]1,3-dioxolan-5- yl)-5-fluoropyrimidin-4-yl)methylamino]propoxy}indolyl)acetic acid 479.2 2.6  1, 15 121 

2-{5-[3-({5-fluoro-2- [4-(trifluoromethyl)phenyl]pyrimidin-4-yl}methylamino)propoxy]indolyl}acetic acid 503.3 3.451, 15 122 

2-(5-{3-[(2-chloro-5- fluoropyrimidin-4-yl)methylamino]propoxy}indolyl)acetic acid 393.2 2.86 1, 15 123 

2-{5-[3-({5-fluoro-2- [4-(trifluoromethoxy)phenyl]pyrimidin-4-yl}methylamino)propoxy]indolyl}acetic acid 519.3 3.341, 15 124 

2-[5-(3-{[2-(4- ethylphenyl)-5-fluoro-pyrimidin-4-yl]amino}propoxy)indolyl]propanoic acid 463.4 2.68 1, 15, 17125 

2-[5-(3-{[5-fluoro-2- (4-methoxyphenyl)pyrimidin-4-yl]amino}propoxy)indolyl]propanoic acid 465.3 2.38 1, 15, 17126 

2-[5-(3-{[5-fluoro-2- (4-fluorophenyl)pyrimidin-4-yl]amino}propoxy)indolyl]propanoic acid 453.1 2.68 1, 15, 17127 

2-[5-(3-{[2-(4- ethylphenyl)-5-fluoro- pyrimidin-4-yl]methyl-amino}propoxy)indolyl]propanoic acid 477.2 2.72 1, 15, 17 128 

2-[5-(3-{[5-fluoro-2- (4-methoxyphenyl) pyrimidin-4-yl]methyl-amino}propoxy)indolyl]propanoic acid 477.2 3.04 1, 15, 17 129 

2-[5-(3-{[5-fluoro-2- (4-fluorophenyl) pyrimidin-4-yl]methyl-amino}propoxy)indolyl]propanoic acid 467.2 2.99 1, 15, 17Methods of Use

As used herein, various terms are defined below.

When introducing elements of the present invention or the preferredembodiment(s) thereof, the articles “a,” “an,” “the,” and “said” areintended to mean that there are one or more of the elements. The terms“comprising,” “including,” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

The term “subject” as used herein includes mammals (e.g., humans andanimals).

The term “treatment” includes any process, action, application, therapy,or the like, wherein a subject, including a human being, is providedmedical aid with the object of improving the subject's condition,directly or indirectly, or slowing the progression of a condition ordisorder in the subject.

The term “combination therapy” or “co-therapy” means the administrationof two or more therapeutic agents to treat a diabetic condition and/ordisorder. Such administration encompasses co-administration of two ormore therapeutic agents in a substantially simultaneous manner, such asin a single capsule having a fixed ratio of active ingredients or inmultiple, separate capsules for each inhibitor agent. In addition, suchadministration encompasses use of each type of therapeutic agent in asequential manner.

The phrase “therapeutically effective” means the amount of each agentadministered that will achieve the goal of improvement in a diabeticcondition or disorder severity, while avoiding or minimizing adverseside effects associated with the given therapeutic treatment.

The term “pharmaceutically acceptable” means that the subject item isappropriate for use in a pharmaceutical product.

The compounds of the present invention may be employed in the treatmentof diabetes, including both type 1 and type 2 diabetes (non-insulindependent diabetes mellitus). Such treatment may also delay the onset ofdiabetes and diabetic complications. The compounds may be used toprevent subjects with impaired glucose tolerance from proceeding todevelop type 2 diabetes. Other diseases and conditions that may betreated or prevented using compounds of the invention in methods of theinvention include: Maturity-Onset Diabetes of the Young (MODY) (Herman,et al., Diabetes 43:40, 1994); Latent Autoimmune Diabetes Adult (LADA)(Zimmet, et al., Diabetes Med. 11:299, 1994); impaired glucose tolerance(IGT) (Expert Committee on Classification of Diabetes Mellitus, DiabetesCare 22 (Supp. 1):S5, 1999); impaired fasting glucose (IFG) (Charles, etal., Diabetes 40:796, 1991); gestational diabetes (Metzger, Diabetes,40:197, 1991); and metabolic syndrome X.

The compounds of the present invention may also be effective in suchdisorders as obesity, and in the treatment of atherosclerotic disease,hyperlipidemia, hypercholesteremia, low HDL levels, hypertension,cardiovascular disease (including atherosclerosis, coronary heartdisease, coronary artery disease, and hypertension), cerebrovasculardisease and peripheral vessel disease.

The compounds of the present invention may also be useful for treatingphysiological disorders related to, for example, cell differentiation toproduce lipid accumulating cells, regulation of insulin sensitivity andblood glucose levels, which are involved in, for example, abnormalpancreatic beta-cell function, insulin secreting tumors and/orautoimmune hypoglycemia due to autoantibodies to insulin, autoantibodiesto the insulin receptor, or autoantibodies that are stimulatory topancreatic beta-cells, macrophage differentiation which leads to theformation of atherosclerotic plaques, inflammatory response,carcinogenesis, hyperplasia, adipocyte gene expression, adipocytedifferentiation, reduction in the pancreatic beta-cell mass, insulinsecretion, tissue sensitivity to insulin, liposarcoma cell growth,polycystic ovarian disease, chronic anovulation, hyperandrogenism,progesterone production, steroidogenesis, redox potential and oxidativestress in cells, nitric oxide synthase (NOS) production, increased gammaglutamyl transpeptidase, catalase, plasma triglycerides, HDL, and LDLcholesterol levels, and the like.

Compounds of the invention may also be used in methods of the inventionto treat secondary causes of diabetes (Expert Committee onClassification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1):S5,1999). Such secondary causes include glucocorticoid excess, growthhormone excess, pheochromocytoma, and drug-induced diabetes. Drugs thatmay induce diabetes include, but are not limited to, pyriminil,nicotinic acid, glucocorticoids, phenyloin, thyroid hormone,β-adrenergic agents, α-interferon and drugs used to treat HIV infection.

The compounds of the present invention may be used alone or incombination with additional therapies and/or compounds known to thoseskilled in the art in the treatment of diabetes and related disorders.Combination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of the present inventionand one or more additional agents, as well as administration of thecompound of the present invention and each additional agent in its ownseparate pharmaceutical dosage formulation. For example, a compound ofthe present invention and an agent may be administered to the patienttogether in a single oral dosage composition such as a tablet orcapsule, or each agent may be administered in separate oral dosageformulations.

Where separate dosage formulations are used, the compound of the presentinvention and one or more additional agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

The compounds of the invention may also be administered in combinationwith other known therapies for the treatment of diabetes, including PPARligands (agonists, antagonists), insulin secretagogues, for examplesulfonylurea drugs and non-sulfonylurea secretagogues, α-glucosidaseinhibitors, insulin sensitizers, hepatic glucose output loweringcompounds, insulin and insulin derivatives, and anti-obesity drugs. Suchtherapies may be administered prior to, concurrently with or followingadministration of the compounds of the invention. Insulin and insulinderivatives include both long and short acting forms and formulations ofinsulin. PPAR ligands may include agonists and/or antagonists of any ofthe PPAR receptors or combinations thereof. For example, PPAR ligandsmay include ligands of PPAR-α, PPAR-γ, PPAR-δ or any combination of twoor three of the receptors of PPAR. PPAR ligands include, for example,rosiglitazone, troglitazone, and pioglitazone. Sulfonylurea drugsinclude, for example, glyburide, glimepiride, chlorpropamide,tolbutamide, and glipizide. α-glucosidase inhibitors that may be usefulin treating diabetes when administered with a compound of the inventioninclude acarbose, miglitol, and voglibose. Insulin sensitizers that maybe useful in treating diabetes include PPAR-γ agonists such as theglitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, and the like) and other thiazolidinedione andnon-thiazolidinedione compounds; biguanides such as metformin andphenformin; protein tyrosine phosphatase-1B (PTP-1B) inhibitors;dipeptidyl peptidase IV (DPP-IV) inhibitors, and 11beta-HSD inhibitors.Hepatic glucose output lowering compounds that may be useful in treatingdiabetes when administered with a compound of the invention includeglucagon anatgonists and metformin, such as Glucophage and GlucophageXR. Insulin secretagogues that may be useful in treating diabetes whenadministered with a compound of the invention include sulfonylurea andnon-sulfonylurea drugs: GLP-1, GIP, PACAP, secretin, and derivativesthereof; nateglinide, meglitnide, repaglinide, glibenclamide,glimepiride, chlorpropamide, glipizide. GLP-1 includes derivatives ofGLP-1 with longer half-lives than native GLP-1, such as, for example,fatty-acid derivatized GLP-1 and exendin.

Compounds of the invention may also be used in methods of the inventionin combination with anti-obesity drugs. Anti-obesity drugs include β-3agonists; CB-1 antagonists; neuropeptide Y5 inhibitors; appetitesuppressants, such as, for example, sibutramine (Meridia); and lipaseinhibitors, such as, for example, orlistat (Xenical).

Compounds of the invention may also be used in methods of the inventionin combination with drugs commonly used to treat lipid disorders indiabetic patients. Such drugs include, but are not limited to, HMG-CoAreductase inhibitors, nicotinic acid, lipid lowering drugs (e.g., stanolesters, sterol glycosides such as tiqueside, and azetidinones such asezetimibe), ACAT inhibitors (such as avasimibe), bile acid sequestrants,bile acid reuptake inhibitors, microsomal triglyceride transportinhibitors, and fibric acid derivatives. HMG-CoA reductase inhibitorsinclude, for example, lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rivastatin, itavastatin, cerivastatin, and ZD4522. Fibricacid derivatives include, for example, clofibrate, fenofibrate,bezafibrate, ciprofibrate, beclofibrate, etofibrate, and gemfibrozil.Sequestrants include, for example, cholestyramine, colestipol, anddialkylaminoalkyl derivatives of a cross-linked dextran.

Compounds of the invention may also be used in combination withanti-hypertensive drugs, such as, for example, β-blockers and ACEinhibitors. Examples of additional anti-hypertensive agents for use incombination with the compounds of the present invention include calciumchannel blockers (L-type and T-type; e.g., diltiazem, verapamil,nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists(e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan, neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), and nitrates.

Such co-therapies may be administered in any combination of two or moredrugs (e.g., a compound of the invention in combination with an insulinsensitizer and an anti-obesity drug). Such co-therapies may beadministered in the form of pharmaceutical compositions, as describedbelow.

Based on well known assays used to determine the efficacy for treatmentof conditions identified above in mammals, and by comparison of theseresults with the results of known medicaments that are used to treatthese conditions, the effective dosage of the compounds of thisinvention can readily be determined for treatment of each desiredindication. The amount of the active ingredient (e.g., compounds) to beadministered in the treatment of one of these conditions can vary widelyaccording to such considerations as the particular compound and dosageunit employed, the mode of administration, the period of treatment, theage and sex of the patient treated, and the nature and extent of thecondition treated.

The total amount of the active ingredient to be administered maygenerally range from about 0.0001 mg/kg to about 200 mg/kg, andpreferably from about 0.01 mg/kg to about 200 mg/kg body weight per day.A unit dosage may contain from about 0.05 mg to about 1500 mg of activeingredient, and may be administered one or more times per day. The dailydosage for administration by injection, including intravenous,intramuscular, subcutaneous, and parenteral injections, and use ofinfusion techniques may be from about 0.01 to about 200 mg/kg. The dailyrectal dosage regimen may be from 0.01 to 200 mg/kg of total bodyweight. The transdermal concentration may be that required to maintain adaily dose of from 0.01 to 200 mg/kg.

Of course, the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age of the patient, the diet of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionmay be ascertained by those skilled in the art using conventionaltreatment tests.

The compounds of this invention may be utilized to achieve the desiredpharmacological effect by administration to a patient in need thereof inan appropriately formulated pharmaceutical composition. A patient, forthe purpose of this invention, is a mammal, including a human, in needof treatment for a particular condition or disease. Therefore, thepresent invention includes pharmaceutical compositions which arecomprised of a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound. A pharmaceutically acceptable carrier isany carrier which is relatively non-toxic and innocuous to a patient atconcentrations consistent with effective activity of the activeingredient so that any side effects ascribable to the carrier do notvitiate the beneficial effects of the active ingredient. Atherapeutically effective amount of a compound is that amount whichproduces a result or exerts an influence on the particular conditionbeing treated. The compounds described herein may be administered with apharmaceutically-acceptable carrier using any effective conventionaldosage unit forms, including, for example, immediate and timed releasepreparations, orally, parenterally, topically, or the like.

For oral administration, the compounds may be formulated into solid orliquid preparations such as, for example, capsules, pills, tablets,troches, lozenges, melts, powders, solutions, suspensions, or emulsions,and may be prepared according to methods known to the art for themanufacture of pharmaceutical compositions. The solid unit dosage formsmay be a capsule which can be of the ordinary hard- or soft-shelledgelatin type containing, for example, surfactants, lubricants, and inertfillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose, and cornstarchin combination with binders such as acacia, cornstarch, or gelatin;disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum; lubricants intended to improve the flow oftablet granulation and to prevent the adhesion of tablet material to thesurfaces of the tablet dies and punches, for example, talc, stearicacid, or magnesium, calcium or zinc stearate; dyes; coloring agents; andflavoring agents intended to enhance the aesthetic qualities of thetablets and make them more acceptable to the patient. Suitableexcipients for use in oral liquid dosage forms include diluents such aswater and alcohols, for example, ethanol, benzyl alcohol, andpolyethylene alcohols, either with or without the addition of apharmaceutically acceptable surfactant, suspending agent, or emulsifyingagent. Various other materials may be present as coatings or tootherwise modify the physical form of the dosage unit. For instancetablets, pills or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent, and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example, those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived from fattyacids and hexitol anhydrides, for example, sorbitan monooleate, and (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil, or coconut oil; or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol, or sucrose. Suchformulations may also contain a demulcent, and preservative, flavoringand coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intramuscularly, orinterperitoneally, as injectable dosages of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichmay be a sterile liquid or mixture of liquids such as water, saline,aqueous dextrose and related sugar solutions; an alcohol such asethanol, isopropanol, or hexadecyl alcohol; glycols such as propyleneglycol or polyethylene glycol; glycerol ketals such as2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such aspoly(ethyleneglycol) 400; an oil; a fatty acid; a fatty acid ester orglyceride; or an acetylated fatty acid glyceride with or without theaddition of a pharmaceutically acceptable surfactant such as a soap or adetergent, suspending agent such as pectin, carbomers, methycellulose,hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifyingagent and other pharmaceutical adjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum, and mineral oil. Suitable fattyacids include oleic acid, stearic acid, and isostearic acid. Suitablefatty acid esters are, for example, ethyl oleate and isopropylmyristate. Suitable soaps include fatty alkali metal, ammonium, andtriethanolamine salts and suitable detergents include cationicdetergents, for example, dimethyl dialkyl ammonium halides, alkylpyridinium halides, and alkylamine acetates; anionic detergents, forexample, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, andmonoglyceride sulfates, and sulfosuccinates; nonionic detergents, forexample, fatty amine oxides, fatty acid alkanolamides, andpolyoxyethylenepolypropylene copolymers; and amphoteric detergents, forexample, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternaryammonium salts, as well as mixtures.

The parenteral compositions of this invention may typically contain fromabout 0.5% to about 25% by weight of the active ingredient in solution.Preservatives and buffers may also be used advantageously. In order tominimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) of from about 12 to about 17. Thequantity of surfactant in such formulation ranges from about 5% to about15% by weight. The surfactant can be a single component having the aboveHLB or can be a mixture of two or more components having the desiredHLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadecaethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, and isotonic sodium chloride solution. Inaddition, sterile fixed oils are conventionally employed as solvents orsuspending media. For this purpose, any bland, fixed oil may be employedincluding synthetic mono or diglycerides. In addition, fatty acids suchas oleic acid may be used in the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the drug (e.g., compound) with a suitablenon-irritation excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such material are, for example, cocoa butter andpolyethylene glycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, incorporated herein by reference). Such patches may beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. For example, directtechniques for administering a drug directly to the brain usuallyinvolve placement of a drug delivery catheter into the patient'sventricular system to bypass the blood-brain barrier. One suchimplantable delivery system, used for the transport of agents tospecific anatomical regions of the body, is described in U.S. Pat. No.5,011,472, incorporated herein by reference.

The compositions of the invention may also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Any of thecompositions of this invention may be preserved by the addition of anantioxidant such as ascorbic acid or by other suitable preservatives.Conventional procedures for preparing such compositions in appropriatedosage forms can be utilized.

Commonly used pharmaceutical ingredients which may be used asappropriate to formulate the composition for its intended route ofadministration include: acidifying agents, for example, but are notlimited to, acetic acid, citric acid, fumaric acid, hydrochloric acid,nitric acid; and alkalinizing agents such as, but are not limited to,ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine.

Other pharmaceutical ingredients include, for example, but are notlimited to, adsorbents (e.g., powdered cellulose and activatedcharcoal); aerosol propellants (e.g., carbon dioxide, CCl₂F₂,F₂ClC—CClF₂ and CClF₃); air displacement agents (e.g., nitrogen andargon); antifungal preservatives (e.g., benzoic acid, butylparaben,ethylparaben, methylparaben, propylparaben, sodium benzoate);antimicrobial preservatives (e.g., benzalkonium chloride, benzethoniumchloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol,phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal);antioxidants (e.g., ascorbic acid, ascorbyl palmitate, butylatedhydroxyanisole, butylated hydroxytoluene, hypophosphorus acid,monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite,sodium formaldehyde sulfoxylate, sodium metabisulfite); bindingmaterials (e.g., block polymers, natural and synthetic rubber,polyacrylates, polyurethanes, silicones and styrene-butadienecopolymers); buffering agents (e.g., potassium metaphosphate, potassiumphosphate monobasic, sodium acetate, sodium citrate anhydrous and sodiumcitrate dihydrate); carrying agents (e.g., acacia syrup, aromatic syrup,aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, cornoil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chlorideinjection and bacteriostatic water for injection); chelating agents(e.g., edetate disodium and edetic acid); colorants (e.g., FD&C Red No.3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5,D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red);clarifying agents (e.g., bentonite); emulsifying agents (but are notlimited to, acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate,lecithin, sorbitan monooleate, polyethylene 50 stearate); encapsulatingagents (e.g., gelatin and cellulose acetate phthalate); flavorants(e.g., anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermintoil and vanillin); humectants (e.g., glycerin, propylene glycol andsorbitol); levigating agents (e.g., mineral oil and glycerin); oils(e.g., arachis oil, mineral oil, olive oil, peanut oil, sesame oil andvegetable oil); ointment bases (e.g., lanolin, hydrophilic ointment,polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, whiteointment, yellow ointment, and rose water ointment); penetrationenhancers (transdermal delivery) (e.g., monohydroxy or polyhydroxyalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas); plasticizers (e.g., diethyl phthalate andglycerin); solvents (e.g., alcohol, corn oil, cottonseed oil, glycerin,isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water,water for injection, sterile water for iniection and sterile water forirrigation); stiffening agents (e.g., cetyl alcohol, cetyl esters wax,microcrystalline wax, paraffin, stearyl alcohol, white wax and yellowwax); suppository bases (e.g., cocoa butter and polyethylene glycols(mixtures)); surfactants (e.g., benzalkonium chloride, nonoxynol 10,oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitanmonopalmitate); suspending agents (e.g., agar, bentonite, carbomers,carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose,tragacanth and veegum); sweetening e.g., aspartame, dextrose, glycerin,mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose);tablet anti-adherents (e.g., magnesium stearate and talc); tabletbinders (e.g., acacia, alginic acid, carboxymethylcellulose sodium,compressible sugar, ethylcellulose, gelatin, liquid glucose,methylcellulose, povidone and pregelatinized starch); tablet and capsulediluents (e.g., dibasic calcium phosphate, kaolin, lactose, mannitol,microcrystalline cellulose, powdered cellulose, precipitated calciumcarbonate, sodium carbonate, sodium phosphate, sorbitol and starch);tablet coating agents (e.g., liquid glucose, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose,ethylcellulose, cellulose acetate phthalate and shellac); tablet directcompression excipients (e.g., dibasic calcium phosphate); tabletdisintegrants (e.g., alginic acid, carboxymethylcellulose calcium,microcrystalline cellulose, polacrillin potassium, sodium alginate,sodium starch glycollate and starch); tablet glidants (e.g., colloidalsilica, corn starch and talc); tablet lubricants (e.g., calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate); tablet/capsule opaquants (e.g., titanium dioxide); tabletpolishing agents (e.g., carnuba wax and white wax); thickening agents(e.g., beeswax, cetyl alcohol and paraffin); tonicity agents (e.g.,dextrose and sodium chloride); viscosity increasing agents (e.g.,alginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, povidone, sodium alginate and tragacanth); and wettingagents (e.g., heptadecaethylene oxycetanol, lecithins, polyethylenesorbitol monooleate, polyoxyethylene sorbitol monooleate, andpolyoxyethylene stearate).

The compounds described herein may be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. For example, the compounds of this invention can becombined with known anti-obesity, or with known antidiabetic or otherindication agents, and the like, as well as with admixtures andcombinations thereof.

The compounds described herein may also be utilized, in free base formor in compositions, in research and diagnostics, or as analyticalreference standards, and the like. Therefore, the present inventionincludes compositions which are comprised of an inert carrier and aneffective amount of a compound identified by the methods describedherein, or a salt or ester thereof. An inert carrier is any materialwhich does not interact with the compound to be carried and which lendssupport, means of conveyance, bulk, traceable material, and the like tothe compound to be carried. An effective amount of compound is thatamount which produces a result or exerts an influence on the particularprocedure being performed.

Formulations suitable for subcutaneous, intravenous, intramuscular, andthe like; suitable pharmaceutical carriers; and techniques forformulation and administration may be prepared by any of the methodswell known in the art (see, e.g., Remington's Pharmaceutical Sciences,Mack Publishing Co., Easton, Pa., 20^(th) edition, 2000).

It should be apparent to one of ordinary skill in the art that changesand modifications can be made to this invention without departing fromthe spirit or scope of the invention as it is set forth herein.

Evaluation of Compounds

In order that this invention may be better understood, the followingexamples are set forth. These examples are for the purpose ofillustration only, and are not to be construed as limiting the scope ofthe invention in any manner. All publications mentioned herein areincorporated by reference in their entirety.

Demonstration of the activity of the compounds of the present inventionmay be accomplished through in vitro, ex vivo, and in vivo assays thatare well known in the art. For example, to demonstrate the efficacy of apharmaceutical agent for the treatment of diabetes and related disorderssuch as Syndrome X, impaired glucose tolerance, impaired fastingglucose, and hyperinsulinemia or atherosclerotic disease and relateddisorders such as hypertriglyceridemia and hypercholesteremia, thefollowing assays may be used.

Insulin Receptor Binding in 3T3-L1 Cells Treated with Compounds

3T3-L1 cells were seeded at 9300 cells per well in Costar flat bottom TCand incubated for 1 week until they were 2 days post-confluent (e.g.,cells have reached maximum density). The cells were then treated for 2days with differentiation media (Dulbecco's Modified Eagle Medium(DMEM), 100 μg/ml Penicillin/Streptomycin, 2 mM L-Glutamine, 10% FetalBovine Serum) containing 0.5 μM human Insulin-like Growth Factor (IGF-1)and test compounds. After treatment, the media was replaced withdifferentiation media, and the cells were incubated for 4 days. Thecells were then assayed for insulin receptor activity. After washing thecells with buffer, they were incubated with 0.1 nM ¹²⁵I-insulin and(+/−) 100 nM unlabeled insulin, and incubated at rt for 1 hour. Thecells were then washed 3× with buffer, dissolved with 1N NaOH, andcounted on a gamma counter. An EC50 value was determined if a plateauwas attained and percent maximum stimulation was assessed.

In Vivo Assays

Method for Measuring Blood Glucose Levels

db/db mice (obtained from Jackson Laboratories, Bar Harbor, Me.) arebled (by either eye or tail vein) and grouped according to equivalentmean blood glucose levels. They are dosed orally (by gavage in apharmaceutically acceptable vehicle) with the test compound once dailyfor 14 days. At this point, the animals are bled again by eye or tailvein and blood glucose levels are determined. In each case, glucoselevels are measured with a Glucometer Elite XL (Bayer Corporation,Elkhart, Ind.).

Method for Measuring Triglyceride Levels

hApoA1 mice (obtained from Jackson Laboratories, Bar Harbor, Me.) arebled (by either eye or tail vein) and grouped according to equivalentmean serum triglyceride levels. They are dosed orally (by gavage in apharmaceutically acceptable vehicle) with the test compound once dailyfor 8 days. The animals are then bled again by eye or tail vein, andserum triglyceride levels are determined. In each case, triglyceridelevels are measured using a Technicon Axon Autoanalyzer (BayerCorporation, Tarrytown, N.Y.).

Method for Measuring HDL-Cholesterol Levels

To determine plasma HDL-cholesterol levels, hApoA1 mice are bled andgrouped with equivalent mean plasma HDL-cholesterol levels. The mice areorally dosed once daily with vehicle or test compound for 7 days, andthen bled again on day 8. Plasma is analyzed for HDL-cholesterol usingthe Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, Calif.).

Method for Measuring Total Cholesterol, HDL-Cholesterol, Triglycerides,and Glucose Levels

In another in vivo assay, obese rats are bled, then orally dosed oncedaily with vehicle or test compound for 4 weeks, and then bled again.Serum is analyzed for total cholesterol, HDL-cholesterol, triglycerides,and glucose using the Synchron Clinical System (CX4) (Beckman Coulter,Fullerton, Calif.). Lipoprotein subclass analysis is performed by NMRspectroscopy as described by Oliver et al., (Proc. Natl. Acad. Sci. USA98:5306-5311, 2001).

Method for Measuring an Effect on Cardiovascular Parameters

Cardiovascular parameters (e.g., heart rate and blood pressure) are alsoevaluated. SHR rats are orally dosed once daily with vehicle or testcompound for 2 weeks. Blood pressure and heart rate are determined usinga tail-cuff method as described by Grinsell et al., (Am. J. Hypertens.13:370-375, 2000).

It should be apparent to one of ordinary skill in the art that changesand modifications can be made to this invention without departing fromthe spirit or scope of the invention as it is set forth herein.

1. A compound of Formula (Ia)

wherein R¹ is H, C₁-C₆ alkyl, or benzyl; R² is H or C₁-C₆ alkyl; R³ is Hor C₁-C₄alkyl; Y is O or NR⁵; R⁵ is H or C₁-C₆ alkyl optionallysubstituted with C₃-C₆ cycloalkyl; n is 2, 3, or 4; Ar is a ring radicalselected from phenyl and a 6-membered heteroaryl ring containing up tothree N atoms, said Ar being optionally substituted at any availableposition by 1 to 5 independently selected R⁶ groups, and optionallyfused to a 5- or 6-membered saturated carbocyclic ring, a 5- or6-membered unsaturated carbocyclic ring, or a 5- or 6-memberedheterocyclic ring containing up to 3 additional heteroatoms selectedfrom N, O, and S, wherein said fused ring may be optionally substitutedat any available position by 1-4 independently selected R⁷ groups; R⁶ isselected from the group OH, SH, halo, CN, NO₂, C(═O)OH, C(═O)—OC₁-C₆alkyl, C(═O)—OC₃-C₆ cycloalkyl, NR⁸R⁹, C(═O)NR⁸R⁹, C(═S)NR₈R⁹, C₁-C₆alkyl optionally substituted with halo, OH, NR⁸R⁹, or C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ thioalkyl, C₂-C₆ alkenyl, C₁-C₆haloalkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, phenoxy optionallysubstituted on the phenyl ring with halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy,and a mono or bicyclic ring radical selected from the group consistingof phenyl optionally fused to a 5- or 6-membered saturated or partiallyunsaturated carbocyclic ring, or a 5- or 6-membered saturated orpartially unsaturated heterocyclic ring containing from 1-3 heteroatomsselected from N, O, and S, and a 5- or 6-membered heterocyclic ringradical containing up to 4 heteroatoms selected from N, O, or S,optionally fused to a 5- or 6-membered saturated or partiallyunsaturated carbocyclic ring, or a 5- or 6-membered saturated orpartially unsaturated heterocyclic ring containing from 1-3 heteroatomsselected from N, O, and S, said mono or bicyclic ring radical beingoptionally substituted with up to 5 of the following groups halo,hydroxy, oxo, CN, C₁-C₆alkyl optionally substituted with halo, OH,NR⁸R⁹, or C₁-C₆ alkoxy. C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkylC₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, C₁-C₆ acyl,C(═O)OH, CH₂C(═O)OH, NR⁸R⁹ C(═O)NR⁸R⁹, C(═O)OC₁-C₆ alkyl, andC(═O)OC₃-C₆ cycloalkyl; R⁷ is selected from the group oxo, hydroxy,halo, CN, NR⁸R⁹, C₁-C₆ alkyl optionally substituted with OH, NR⁸R⁹, orC₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, C₁-C₆haloalkoxy, C₃-C₆ cycloalkyl, and C₃-C₆ cycloalkoxy; R⁸ and R⁹ areindependently selected from H, C₁-C₆ alkyl optionally substituted withC₃-C₆ cycloalkyl, C₁-C₆ acyl, benzyl optionally substituted with halo,C₁-C₆ alkoxy, (C₁-C₆)alkyl, CN, NH₂, N[(C₁-C₃)alkyl]₂, NO₂, or CF₃,C₃-C₆ cycloalkyl, and phenyl optionally substituted with halo,C₁-C₆alkoxy, (C₁-C₆)alkyl, CN, N[(C₁-C₃)alkyl]₂, NO₂, or CF₃, or R⁸ andR⁹ may be taken together with the nitrogen atom to which they areattached to form a 5- or 6-membered heterocyclic ring optionallyinterrupted by NR⁵ or O; or the pharmacologically acceptable esters andsalts thereof.
 2. The compound of claim 1, wherein R¹ is H; Y is O; n is2 or 3; Ar is phenyl, said phenyl being optionally substituted at anyavailable position by 1 to 5 independently selected R⁶ groups, andoptionally fused to a 5- or 6-membered saturated carbocyclic ring, a 5-or 6-membered unsaturated carbocyclic ring, or a 5- or 6-memberedheterocyclic ring containing up to 3 additional heteroatoms selectedfrom N, O, and S, wherein said fused ring may be optionally substitutedat any available position by 14 independently selected R⁷ groups; andR², R³, R⁶, R⁷, R⁸, and R⁹ are as defined in claim
 1. 3. The compound ofclaim 2, wherein Ar is phenyl, said phenyl being optionally substitutedat any available position by 1 to 5 independently selected R⁶ groups,and fused to a 5- or 6-membered saturated carbocyclic ring, a 5- or6-membered unsaturated carbocyclic ring, or a 5- or 6-memberedheterocyclic ring containing up to 3 additional heteroatoms selectedfrom N, O, and S, wherein said fused ring may be optionally substitutedat any available position by 1-4 independently selected R⁷ groups. 4.The compound of claim 1, wherein R¹ is H; Y is O; n is 2 or 3; Ar isphenyl, said phenyl being optionally substituted at any availableposition by 1 to 5 independently selected R⁶ groups, and one or moresubstituents is a 5- or 6-membered heterocyclic ring radical containingup to 4 heteroatoms selected from N, O, or S, optionally fused to a 5-or 6-membered saturated or partially unsaturated carbocyclic ring, or a5- or 6-membered saturated or partially unsaturated heterocyclic ringcontaining from 1-3 heteroatoms selected from N, O, and S, said mono orbicyclic ring radical being optionally substituted with up to 5 of thefollowing groups halo, hydroxy, oxo, CN, C₁-C₆alkyl optionallysubstituted with halo, OH, NR⁸R⁹, or C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, C₁-C₆ thioalkyl C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₃-C₆cycloalkoxy, C₁-C₆ acyl, C(═O)OH, CH₂C(═O)OH, NR⁸R⁹ C(═O)NR⁸R⁹,C(═O)OC₁-C₆alkyl, and C(═O)OC₃-C₆ cycloalkyl; and R², R³, R⁶, R⁷, R⁸,and R⁹ are as defined in claim
 1. 5. The compound of claim 1, wherein R¹is H; Y is O; n is 2 or 3; Ar is a 6-membered heteroaryl ring containingup to three N atoms, said heteroaryl being optionally substituted at anyavailable position by 1 to 5 independently selected R⁶ groups, andoptionally fused to a 5- or 6-membered saturated carbocyclic ring, a 5-or 6-membered unsaturated carbocyclic ring, or a 5- or 6-memberedheterocyclic ring containing up to 3 additional heteroatoms selectedfrom N, O, and S, wherein said fused ring may be optionally substitutedat any available position by 14 independently selected R⁷ groups; andR², R³, R⁶, R⁷, R⁸, and R⁹ are as defined in claim
 1. 6. The compound ofclaim 1, wherein R¹ is H; Y is NR⁵; n is 2 or 3; Ar is a 6-memberedheteroaryl ring containing up to three N atoms, said heteroaryl beingoptionally substituted at any available position by 1 to 5 independentlyselected R⁶ groups, and optionally fused to a 5- or 6-membered saturatedcarbocyclic ring, a 5- or 6-membered unsaturated carbocyclic ring, or a5- or 6-membered heterocyclic ring containing up to 3 additionalheteroatoms selected from N, O, and S, wherein said fused ring may beoptionally substituted at any available position by 14 independentlyselected R⁷ groups; and R², R³, R⁵, R⁶, R⁷, R⁸, and R⁹ are as defined inclaim
 1. 7. A compound of Formula (Ib)

wherein R¹ is H, C₁-C₆ alkyl, or benzyl; R² is H or C₁-C₆ alkyl; R⁴ isH, C₁-C₄ alkyl, or C₁-C₄ acyl; Y is O or NR⁵; R⁵ is H or C₁-C₆ alkyloptionally substituted with C₃-C₆ cycloalkyl; n is 2, 3, or 4; Ar is aring radical selected from phenyl and a 6-membered heteroaryl ringcontaining up to three N atoms, said Ar being optionally substituted atany available position by 1 to 5 independently selected R⁶ groups, andoptionally fused to a 5- or 6-membered saturated carbocyclic ring, a 5-or 6-membered unsaturated carbocyclic ring, or a 5- or 6-memberedheterocyclic ring containing up to 3 additional heteroatoms selectedfrom N, O, and S, wherein said fused ring may be optionally substitutedat any available position by 14 independently selected R⁷ groups; R⁶ isselected from the group OH, SH, halo, CN, NO₂, C(═O)OH, C(═O)—OC₁-C₆alkyl, C(═O)—OC₃-C₆ cycloalkyl, NR⁸R⁹, C(═O)NR⁸R⁹, C(═S)NR⁸R⁹, C₁-C₆alkyl optionally substituted with halo, OH, NR⁸R⁹, or C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ thioalkyl, C₂-C₆ alkenyl, C₁-C₆haloalkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, phenoxy optionallysubstituted on the phenyl ring with halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy,and a mono or bicyclic ring radical selected from the group consistingof phenyl optionally fused to a 5- or 6-membered saturated or partiallyunsaturated carbocyclic ring, or a 5- or 6-membered saturated orpartially unsaturated heterocyclic ring containing from 1-3 heteroatomsselected from N, O, and S, and a 5- or 6-membered heterocyclic ringradical containing up to 4 heteroatoms selected from N, O, or S,optionally fused to a 5- or 6-membered saturated or partiallyunsaturated carbocyclic ring, or a 5- or 6-membered saturated orpartially unsaturated heterocyclic ring containing from 1-3 heteroatomsselected from N, O, and S, said mono or bicyclic ring radical beingoptionally substituted with up to 5 of the following groups halo,hydroxy, oxo, CN, C₁-C₆ alkyl optionally substituted with halo, OH,NR⁸R⁹, or C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkylC₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, C₁-C₆ acyl,C(═O)OH, CH₂C(═O)OH, NR⁸R⁹ C(═O)NR¹R⁹, C(═O)OC₁-C₆alkyl, and C(═O)OC₃-C₆cycloalkyl; R⁷ is selected from the group oxo, hydroxy, halo, CN, NR⁸R⁹,C₁-C₆ alkyl optionally substituted with OH, NR⁸R⁹, or C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, C₁-C₆ haloalkoxy, C₃-C₆cycloalkyl, and C₃-C₆ cycloalkoxy; R⁶ and R⁹ are independently selectedfrom H, C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl, C₁-C₆acyl, benzyl optionally substituted with halo, C₁-C₆ alkoxy,(C₁-C₆)alkyl, CN, NH₂, N[(C₁-C₃)alkyl]₂, NO₂, or CF₃, C₃-C₆ cycloalkyl,and phenyl optionally substituted with halo, C₁-C₆ alkoxy, (C₁-C₆)alkyl,CN, N[(C₁-C₃)alkyl]₂, NO₂, or CF₃, or R⁸ and R⁹ may be taken togetherwith the nitrogen atom to which they are attached to form a 5- or6-membered heterocyclic ring optionally interrupted by NR⁵ or O; or thepharmacologically acceptable esters and salts thereof.
 8. A compoundselected from the group consisting of(5-{3-[4-(4,5,6,7-tetrahydro-benzooxazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-aceticacid;(5-{3-[4-(4-ethyl-oxazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-aceticacid;(5-{3-[2-propyl-4-(4,5,6,7-tetrahydro-benzooxazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-aceticacid;(5-{3-[4-(4-tert-butyl-oxazol-2-yl)-2-propyl-phenoxy]-propoxy}-3-methylindolyl)-aceticacid;2-(5-{3-[4-(4-ethyl(1,3-oxazol-2-yl))-2-propylphenoxy]propoxy}-3-methylindolyl)aceticacid;2-{3-methyl-5-[3-(2-propyl-4-(4,5,6,7-tetrahydrobenzoxazol-2-yl)phenoxy)propoxy]indolyl}propanoicacid;2-{5-[3-(2-methoxy-4-(4,5,6,7-tetrahydrobenzothiazol-2-yl)phenoxy)propoxy]indolyl}aceticacid;(5-{3-[4-(4-ethyl-thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-aceticacid;2-{5-[3-(2-propyl-4-(4,5,6,7-tetrahydrobenzothiazol-2-yl)phenoxy)propoxy]indolyl}aceticacid;2-(5-{3-[4-(4-ethoxy-5-methyl(1,3-thiazol-2-yl))-2-propylphenoxy]propoxy}indolyl)aceticacid;2-[5-(3-{4-[5-(N,N-dimethylcarbamoyl)-4-methyl(1,3-thiazol-2-yl)]-2-propylphenoxy}propoxy)indolyl]aceticacid;2-{5-[3-(2-propyl-4-(1,3-thiazol-2-yl)phenoxy)propoxy]indolyl}aceticacid;(5-{3-[4-(6,7-dihydro-5H-pyrano[2,3-d]thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-aceticacid;2-(5-{3-[4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-propionicacid;(2S)-2-(5-{3-[4-ethoxy-5-methyl-thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-propionicacid;(2R)-2-(5-{3-[4-(4-ethoxy-5-methyl-thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-propionicacid;2-{3-methyl-5-[3-(2-propyl-4-(4,5,6,7-tetrahydrobenzothiazol-2-yl)phenoxy)propoxy]indolyl}aceticacid;(2S)-2-(3-methyl-5-{3-[2-propyl-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-propionicacid; and(3-ethyl-5-{3-[2-propyl-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-aceticacid.
 9. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1 or 7, or a pharmaceuticallyacceptable salt or ester, in combination with a pharmaceuticallyacceptable carrier.
 10. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 or 7, or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier and one or more pharmaceuticalagents.
 11. The pharmaceutical composition of claim 10, wherein thepharmaceutical agent is PPAR ligands, insulin secretagogues,sulfonylurea drugs, α-glucosidase inhibitors, insulin sensitizers,hepatic glucose output lowering compounds, insulin and insulinderivatives, biguanides, protein tyrosine phosphatase-1B, dipeptidylpeptidase IV, 11beta-HSD inhibitors, anti-obesity drugs, HMG-CoAreductase inhibitors, nicotinic acid, lipid lowering drugs, ACATinhibitors, bile acid sequestrants, bile acid reuptake inhibitors,microsomal triglyceride transport inhibitors, fibric acid derivatives,β-blockers, ACE inhibitors, calcium channel blockers, diuretics, renininhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutralendopeptidase inhibitors, vasopepsidase inhibitors, and nitrates.
 12. Amethod of treating or preventing a disease or condition selected fromthe group consisting of diabetes (type I or type 2), maturity-onsetdiabetes of the young (MODY), latent autoimmune diabetes adult (LADA),impaired glucose tolerance (IGT), impaired fasting glucose (IFG),gestational diabetes, and metabolic syndrome X, comprising administeringto a mammal an effective amount of a compound of claim 1 or
 7. 13. Themethod of claim 12, further comprising administering a PPAR ligand, aninsulin sensitizer, a sulfonylurea, an insulin secretagogue, a hepaticglucose output lowering compound, an α-glucosidase inhibitor,biguanides, protein tyrosine phosphatase-1B (PTP-1B) inhibitors,dipeptidyl peptidase IV, 11beta-HSD inhibitors, insulin or insulinderivatives in combination with said compound of claim 1 or
 7. 14. Themethod of claim 12, further comprising administering an anti-obesitydrug in combination with said compound of claim 1 or
 7. 15. The methodof claim 14, wherein the anti-obesity drug is selected from β-3agonists, CB-1 antagonists, neuropeptide Y5 inhibitors, ciliaryneurotrophic factor and derivatives, appetite suppressants, and lipaseinhibitors.
 16. A method of treating or preventing lipid disorders indiabetic patients, comprising administering to a mammal an effectiveamount of a compound of claim 1 or 7 in combination with HMG-CoAreductase inhibitors, nicotinic acid, fatty acid lowering compounds,lipid lowering drugs, ACAT inhibitors, bile acid sequestrants, bile acidreuptake inhibitors, microsomal triglyceride transport inhibitors, orfibric acid derivatives.
 17. A method of treating or preventinghypertension in diabetic patients, comprising administering to a mammalan effective amount of a compound of claim 1 or 7 in combination withβ-blockers, ACE inhibitors, calcium channel blockers, diuretics, renininhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutralendopeptidase (NEP) inhibitors, vasopepsidase inhibitors, and nitrates.18. A medicament comprising a compound according to any one of claimsclaim 1 to
 8. 19. A medicament comprising a compound according to anyone of claims claim 1 to 8 in combination with at least onepharmaceutically acceptable, pharmaceutically safe carrier orexcipient/diluent/adjuvans.
 20. A medicament consisting of a compoundaccording to any one of claims claim 1 to 8 in combination with PPARligands, insulin secretagogues, sulfonylurea drugs, α-glucosidaseinhibitors, insulin sensitizers, hepatic glucose output loweringcompounds, insulin and insulin derivatives, biguanides, protein tyrosinephosphatase-1B, dipeptidyl peptidase IV, 11beta-HSD inhibitors,anti-obesity drugs, HMG-CoA reductase inhibitors, nicotinic acid, lipidlowering drugs, ACAT inhibitors, bile acid sequestrants, bile acidreuptake inhibitors, microsomal triglyceride transport inhibitors,fibric acid derivatives, β-blockers, ACE inhibitors, calcium channelblockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ETreceptor antagonists, neutral endopeptidase inhibitors, vasopepsidaseinhibitors, and nitrates.
 21. A process for preparing a medicamentaccording to claim 19, comprising combining at least one compoundaccording to any one of claims claim 1 to 8 with at least onepharmaceutically acceptable, pharmaceutically safe carrier orexcipient/diluent/adjuvans, mixing the combination and bringing thecombination into a suitable administration form.
 22. The use of acompound according to any one of claims claim 1 to 8 for manufacturing amedicament for the treatment and/or prophylaxis of diabetes (type 1 ortype 2), maturity-onset diabetes of the young (MODY), latent autoimmunediabetes adult (LADA), impaired glucose tolerance (IGT), impairedfasting glucose (IFG), gestational diabetes, and metabolic syndrome X.